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1. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

Author

Hollestelle A, van der Baan FH, Berchuck A, Johnatty SE, Aben KK, Agnarsson BA, Aittomäki K, Alducci E, Andrulis IL, Anton-Culver H, Antonenkova NN, Antoniou AC, Apicella C, Arndt V, Arnold N, Arun BK, Arver B, Ashworth A, Baglietto L, Balleine R, Bandera EV, Barrowdale D, Bean YT, Beckmann L, Beckmann MW, Benitez J, Berger A, Berger R, Beuselinck B, Bisogna M, Bjorge L, Blomqvist C, Bogdanova NV, Bojesen A, Bojesen SE, Bolla MK, Bonanni B, Brand JS, Brauch H, Brenner H, Brinton L, Brooks-Wilson A, Bruinsma F, Brunet J, Brüning T, Budzilowska A, Bunker CH, Burwinkel B, Butzow R, Buys SS, Caligo MA, Campbell I, Carter J, Chang-Claude J, Chanock SJ, Claes KBM, Collée JM, Cook LS, Couch FJ, Cox A, Cramer D, Cross SS, Cunningham JM, Cybulski C, Czene K, Damiola F, Dansonka-Mieszkowska A, Darabi H, de la Hoya M, deFazio A, Dennis J, Devilee P, Dicks EM, Diez O, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Silva IDS, du Bois A, Dumont M, Dunning AM, Duran M, Easton DF, Eccles D, Edwards RP, Ehrencrona H, Ejlertsen B, Ekici AB, Ellis SD, Engel C, Eriksson M, Fasching PA, Feliubadalo L, Figueroa J, Flesch-Janys D, Fletcher O, Fontaine A, Fortuzzi S, Fostira F, Fridley BL, Friebel T, Friedman E, Friel G, Frost D, Garber J, García-Closas M, Gayther SA, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goodman MT, Gore M, Greene MH, Grip M, Gronwald J, Gschwantler Kaulich D, Guénel P, Guzman SR, Haeberle L, Haiman CA, Hall P, Halverson SL, Hamann U, Hansen TVO, Harter P, Hartikainen JM, Healey S, Hein A, Heitz F, Henderson BE, Herzog J, T Hildebrandt MA, Høgdall CK, Høgdall E, Hogervorst FBL, Hopper JL, Humphreys K, Huzarski T, Imyanitov EN, Isaacs C, Jakubowska A, Janavicius R, Jaworska K, Jensen A, Jensen UB, Johnson N, Jukkola-Vuorinen A, Kabisch M, Karlan BY, Kataja V, Kauff N, Kelemen LE, Kerin MJ, Kiemeney LA, Kjaer SK, Knight JA, Knol-Bout JP, Konstantopoulou I, Kosma VM, Krakstad C, Kristensen V, Kuchenbaecker KB, Kupryjanczyk J, Laitman Y, Lambrechts D, Lambrechts S, Larson MC, Lasa A, Laurent-Puig P, Lazaro C, Le ND, Le Marchand L, Leminen A, Lester J, Levine DA, Li J, Liang D, Lindblom A, Lindor N, Lissowska J, Long J, Lu KH, Lubinski J, Lundvall L, Lurie G, Mai PL, Mannermaa A, Margolin S, Mariette F, Marme F, Martens JWM, Massuger LFAG, Maugard C, Mazoyer S, McGuffog L, McGuire V, McLean C, McNeish I, Meindl A, Menegaux F, Menéndez P, Menkiszak J, Menon U, Mensenkamp AR, Miller N, Milne RL, Modugno F, Montagna M, Moysich KB, Müller H, Mulligan AM, Muranen TA, Narod SA, Nathanson KL, Ness RB, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nielsen SF, Nordestgaard BG, Nussbaum RL, Odunsi K, Offit K, Olah E, Olopade OI, Olson JE, Olson SH, Oosterwijk JC, Orlow I, Orr N, Orsulic S, Osorio A, Ottini L, Paul J, Pearce CL, Pedersen IS, Peissel B, Pejovic T, Pelttari LM, Perkins J, Permuth-Wey J, Peterlongo P, Peto J, Phelan CM, Phillips KA, Piedmonte M, Pike MC, Platte R, Plisiecka-Halasa J, Poole EM, Poppe B, Pylkäs K, Radice P, Ramus SJ, Rebbeck TR, Reed MWR, Rennert G, Risch HA, Robson M, Rodriguez GC, Romero A, Rossing MA, Rothstein JH, Rudolph A, Runnebaum I, Salani R, Salvesen HB, Sawyer EJ, Schildkraut JM, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schrauder MG, Schumacher F, Schwaab I, Scuvera G, Sellers TA, Severi G, Seynaeve CM, Shah M, Shrubsole M, Siddiqui N, Sieh W, Simard J, Singer CF, Sinilnikova OM, Smeets D, Sohn C, Soller M, Song H, Soucy P, Southey MC, Stegmaier C, Stoppa-Lyonnet D, Sucheston L, Swerdlow A, Tangen IL, Tea MK, Teixeira MR, Terry KL, Terry MB, Thomassen M, Thompson PJ, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Truong T, Tsimiklis H, Tung N, Tworoger SS, Tyrer JP, Vachon CM, Van 't Veer LJ, van Altena AM, Van Asperen CJ, van den Berg D, van den Ouweland AMW, van Doorn HC, Van Nieuwenhuysen E, van Rensburg EJ, Vergote I, Verhoef S, Vierkant RA, Vijai J, Vitonis AF, von Wachenfeldt A, Walsh C, Wang Q, Wang-Gohrke S, Wappenschmidt B, Weischer M, Weitzel JN, Weltens C, Wentzensen N, Whittemore AS, Wilkens LR, Winqvist R, Wu AH, Wu X, Yang HP, Zaffaroni D, Pilar Zamora M, Zheng W, Ziogas A, Chenevix-Trench G, Pharoah PDP, Rookus MA, Hooning MJ, and Goode EL

Subjects
Carcinoma, Ovarian Epithelial, Female, Humans, Breast Neoplasms enzymology, Breast Neoplasms genetics, Neoplasms, Glandular and Epithelial enzymology, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms enzymology, Ovarian Neoplasms genetics, Proto-Oncogene Proteins p21(ras) genetics
Abstract

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370., Methods: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers)., Results: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations., Conclusions: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2016
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2. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

Author

Silvestri V, Barrowdale D, Mulligan AM, Neuhausen SL, Fox S, Karlan BY, Mitchell G, James P, Thull DL, Zorn KK, Carter NJ, Nathanson KL, Domchek SM, Rebbeck TR, Ramus SJ, Nussbaum RL, Olopade OI, Rantala J, Yoon SY, Caligo MA, Spugnesi L, Bojesen A, Pedersen IS, Thomassen M, Jensen UB, Toland AE, Senter L, Andrulis IL, Glendon G, Hulick PJ, Imyanitov EN, Greene MH, Mai PL, Singer CF, Rappaport-Fuerhauser C, Kramer G, Vijai J, Offit K, Robson M, Lincoln A, Jacobs L, Machackova E, Foretova L, Navratilova M, Vasickova P, Couch FJ, Hallberg E, Ruddy KJ, Sharma P, Kim SW, Teixeira MR, Pinto P, Montagna M, Matricardi L, Arason A, Johannsson OT, Barkardottir RB, Jakubowska A, Lubinski J, Izquierdo A, Pujana MA, Balmaña J, Diez O, Ivady G, Papp J, Olah E, Kwong A, Nevanlinna H, Aittomäki K, Perez Segura P, Caldes T, Van Maerken T, Poppe B, Claes KB, Isaacs C, Elan C, Lasset C, Stoppa-Lyonnet D, Barjhoux L, Belotti M, Meindl A, Gehrig A, Sutter C, Engel C, Niederacher D, Steinemann D, Hahnen E, Kast K, Arnold N, Varon-Mateeva R, Wand D, Godwin AK, Evans DG, Frost D, Perkins J, Adlard J, Izatt L, Platte R, Eeles R, Ellis S, Hamann U, Garber J, Fostira F, Fountzilas G, Pasini B, Giannini G, Rizzolo P, Russo A, Cortesi L, Papi L, Varesco L, Palli D, Zanna I, Savarese A, Radice P, Manoukian S, Peissel B, Barile M, Bonanni B, Viel A, Pensotti V, Tommasi S, Peterlongo P, Weitzel JN, Osorio A, Benitez J, McGuffog L, Healey S, Gerdes AM, Ejlertsen B, Hansen TV, Steele L, Ding YC, Tung N, Janavicius R, Goldgar DE, Buys SS, Daly MB, Bane A, Terry MB, John EM, Southey M, Easton DF, Chenevix-Trench G, Antoniou AC, and Ottini L

Subjects
Adult, Aged, Breast Neoplasms pathology, Breast Neoplasms, Male pathology, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Polymorphism, Single Nucleotide, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Breast Neoplasms, Male genetics
Abstract

Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs)., Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database., Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12))., Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Published
2016
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3. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

Author

Blein S, Bardel C, Danjean V, McGuffog L, Healey S, Barrowdale D, Lee A, Dennis J, Kuchenbaecker KB, Soucy P, Terry MB, Chung WK, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Neuhausen SL, Ding YC, Gerdes AM, Ejlertsen B, Nielsen FC, Hansen TV, Osorio A, Benitez J, Conejero RA, Segota E, Weitzel JN, Thelander M, Peterlongo P, Radice P, Pensotti V, Dolcetti R, Bonanni B, Peissel B, Zaffaroni D, Scuvera G, Manoukian S, Varesco L, Capone GL, Papi L, Ottini L, Yannoukakos D, Konstantopoulou I, Garber J, Hamann U, Donaldson A, Brady A, Brewer C, Foo C, Evans DG, Frost D, Eccles D, Douglas F, Cook J, Adlard J, Barwell J, Walker L, Izatt L, Side LE, Kennedy MJ, Tischkowitz M, Rogers MT, Porteous ME, Morrison PJ, Platte R, Eeles R, Davidson R, Hodgson S, Cole T, Godwin AK, Isaacs C, Claes K, De Leeneer K, Meindl A, Gehrig A, Wappenschmidt B, Sutter C, Engel C, Niederacher D, Steinemann D, Plendl H, Kast K, Rhiem K, Ditsch N, Arnold N, Varon-Mateeva R, Schmutzler RK, Preisler-Adams S, Markov NB, Wang-Gohrke S, de Pauw A, Lefol C, Lasset C, Leroux D, Rouleau E, Damiola F, Dreyfus H, Barjhoux L, Golmard L, Uhrhammer N, Bonadona V, Sornin V, Bignon YJ, Carter J, Van Le L, Piedmonte M, DiSilvestro PA, de la Hoya M, Caldes T, Nevanlinna H, Aittomäki K, Jager A, van den Ouweland AM, Kets CM, Aalfs CM, van Leeuwen FE, Hogervorst FB, Meijers-Heijboer HE, Oosterwijk JC, van Roozendaal KE, Rookus MA, Devilee P, van der Luijt RB, Olah E, Diez O, Teulé A, Lazaro C, Blanco I, Del Valle J, Jakubowska A, Sukiennicki G, Gronwald J, Lubinski J, Durda K, Jaworska-Bieniek K, Agnarsson BA, Maugard C, Amadori A, Montagna M, Teixeira MR, Spurdle AB, Foulkes W, Olswold C, Lindor NM, Pankratz VS, Szabo CI, Lincoln A, Jacobs L, Corines M, Robson M, Vijai J, Berger A, Fink-Retter A, Singer CF, Rappaport C, Kaulich DG, Pfeiler G, Tea MK, Greene MH, Mai PL, Rennert G, Imyanitov EN, Mulligan AM, Glendon G, Andrulis IL, Tchatchou S, Toland AE, Pedersen IS, Thomassen M, Kruse TA, Jensen UB, Caligo MA, Friedman E, Zidan J, Laitman Y, Lindblom A, Melin B, Arver B, Loman N, Rosenquist R, Olopade OI, Nussbaum RL, Ramus SJ, Nathanson KL, Domchek SM, Rebbeck TR, Arun BK, Mitchell G, Karlan BY, Lester J, Orsulic S, Stoppa-Lyonnet D, Thomas G, Simard J, Couch FJ, Offit K, Easton DF, Chenevix-Trench G, Antoniou AC, Mazoyer S, Phelan CM, Sinilnikova OM, and Cox DG

Subjects
BRCA1 Protein genetics, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Phylogeny, Risk, Breast Neoplasms genetics, Genes, BRCA2, Genes, Mitochondrial, Heterozygote, Mutation
Abstract

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers., Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals., Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk., Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Published
2015
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4. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Author

Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, Mazoyer S, Chenevix-Trench G, Easton DF, Antoniou AC, Nathanson KL, Laitman Y, Kushnir A, Paluch-Shimon S, Berger R, Zidan J, Friedman E, Ehrencrona H, Stenmark-Askmalm M, Einbeigi Z, Loman N, Harbst K, Rantala J, Melin B, Huo D, Olopade OI, Seldon J, Ganz PA, Nussbaum RL, Chan SB, Odunsi K, Gayther SA, Domchek SM, Arun BK, Lu KH, Mitchell G, Karlan BY, Walsh C, Lester J, Godwin AK, Pathak H, Ross E, Daly MB, Whittemore AS, John EM, Miron A, Terry MB, Chung WK, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Ejlertsen B, Gerdes AM, Hansen Tv, Ramón y Cajal T, Osorio A, Benitez J, Godino J, Tejada MI, Duran M, Weitzel JN, Bobolis KA, Sand SR, Fontaine A, Savarese A, Pasini B, Peissel B, Bonanni B, Zaffaroni D, Vignolo-Lutati F, Scuvera G, Giannini G, Bernard L, Genuardi M, Radice P, Dolcetti R, Manoukian S, Pensotti V, Gismondi V, Yannoukakos D, Fostira F, Garber J, Torres D, Rashid MU, Hamann U, Peock S, Frost D, Platte R, Evans DG, Eeles R, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Hodgson S, Morrison PJ, Walker L, Porteous ME, Kennedy MJ, Izatt L, Adlard J, Donaldson A, Ellis S, Sharma P, Schmutzler RK, Wappenschmidt B, Becker A, Rhiem K, Hahnen E, Engel C, Meindl A, Engert S, Ditsch N, Arnold N, Plendl HJ, Mundhenke C, Niederacher D, Fleisch M, Sutter C, Bartram CR, Dikow N, Wang-Gohrke S, Gadzicki D, Steinemann D, Kast K, Beer M, Varon-Mateeva R, Gehrig A, Weber BH, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Houdayer C, Belotti M, Gauthier-Villars M, Damiola F, Boutry-Kryza N, Lasset C, Sobol H, Peyrat JP, Muller D, Fricker JP, Collonge-Rame MA, Mortemousque I, Nogues C, Rouleau E, Isaacs C, De Paepe A, Poppe B, Claes K, De Leeneer K, Piedmonte M, Rodriguez G, Wakely K, Boggess J, Blank SV, Basil J, Azodi M, Phillips KA, Caldes T, de la Hoya M, Romero A, Nevanlinna H, Aittomäki K, van der Hout AH, Hogervorst FB, Verhoef S, Collée JM, Seynaeve C, Oosterwijk JC, Gille JJ, Wijnen JT, Gómez Garcia EB, Kets CM, Ausems MG, Aalfs CM, Devilee P, Mensenkamp AR, Kwong A, Olah E, Papp J, Diez O, Lazaro C, Darder E, Blanco I, Salinas M, Jakubowska A, Lubinski J, Gronwald J, Jaworska-Bieniek K, Durda K, Sukiennicki G, Huzarski T, Byrski T, Cybulski C, Toloczko-Grabarek A, Złowocka-Perłowska E, Menkiszak J, Arason A, Barkardottir RB, Simard J, Laframboise R, Montagna M, Agata S, Alducci E, Peixoto A, Teixeira MR, Spurdle AB, Lee MH, Park SK, Kim SW, Friebel TM, Couch FJ, Lindor NM, Pankratz VS, Guidugli L, Wang X, Tischkowitz M, Foretova L, Vijai J, Offit K, Robson M, Rau-Murthy R, Kauff N, Fink-Retter A, Singer CF, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Berger A, Greene MH, Mai PL, Imyanitov EN, Toland AE, Senter L, Bojesen A, Pedersen IS, Skytte AB, Sunde L, Thomassen M, Moeller ST, Kruse TA, Jensen UB, Caligo MA, Aretini P, Teo SH, Selkirk CG, Hulick PJ, and Andrulis I

Subjects
Adult, Age of Onset, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Mutation, Ovarian Neoplasms genetics
Abstract

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists., Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2., Design, Setting, and Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk., Exposures: Mutations of BRCA1 or BRCA2., Main Outcomes and Measures: Breast and ovarian cancer risks., Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers., Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Published
2015
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5. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Peterlongo P, Chang-Claude J, Moysich KB, Rudolph A, Schmutzler RK, Simard J, Soucy P, Eeles RA, Easton DF, Hamann U, Wilkening S, Chen B, Rookus MA, Schmidt MK, van der Baan FH, Spurdle AB, Walker LC, Lose F, Maia AT, Montagna M, Matricardi L, Lubinski J, Jakubowska A, Gómez Garcia EB, Olopade OI, Nussbaum RL, Nathanson KL, Domchek SM, Rebbeck TR, Arun BK, Karlan BY, Orsulic S, Lester J, Chung WK, Miron A, Southey MC, Goldgar DE, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Ding YC, Neuhausen SL, Hansen TV, Gerdes AM, Ejlertsen B, Jønson L, Osorio A, Martínez-Bouzas C, Benitez J, Conway EE, Blazer KR, Weitzel JN, Manoukian S, Peissel B, Zaffaroni D, Scuvera G, Barile M, Ficarazzi F, Mariette F, Fortuzzi S, Viel A, Giannini G, Papi L, Martayan A, Tibiletti MG, Radice P, Vratimos A, Fostira F, Garber JE, Donaldson A, Brewer C, Foo C, Evans DG, Frost D, Eccles D, Brady A, Cook J, Tischkowitz M, Adlard J, Barwell J, Walker L, Izatt L, Side LE, Kennedy MJ, Rogers MT, Porteous ME, Morrison PJ, Platte R, Davidson R, Hodgson SV, Ellis S, Cole T, Godwin AK, Claes K, Van Maerken T, Meindl A, Gehrig A, Sutter C, Engel C, Niederacher D, Steinemann D, Plendl H, Kast K, Rhiem K, Ditsch N, Arnold N, Varon-Mateeva R, Wappenschmidt B, Wang-Gohrke S, Bressac-de Paillerets B, Buecher B, Delnatte C, Houdayer C, Stoppa-Lyonnet D, Damiola F, Coupier I, Barjhoux L, Venat-Bouvet L, Golmard L, Boutry-Kryza N, Sinilnikova OM, Caron O, Pujol P, Mazoyer S, Belotti M, Piedmonte M, Friedlander ML, Rodriguez GC, Copeland LJ, de la Hoya M, Segura PP, Nevanlinna H, Aittomäki K, van Os TA, Meijers-Heijboer HE, van der Hout AH, Vreeswijk MP, Hoogerbrugge N, Ausems MG, van Doorn HC, Collée JM, Olah E, Diez O, Blanco I, Lazaro C, Brunet J, Feliubadalo L, Cybulski C, Gronwald J, Durda K, Jaworska-Bieniek K, Sukiennicki G, Arason A, Chiquette J, Teixeira MR, Olswold C, Couch FJ, Lindor NM, Wang X, Szabo CI, Offit K, Corines M, Jacobs L, Robson ME, Zhang L, Joseph V, Berger A, Singer CF, Rappaport C, Kaulich DG, Pfeiler G, Tea MK, Phelan CM, Greene MH, Mai PL, Rennert G, Mulligan AM, Glendon G, Tchatchou S, Andrulis IL, Toland AE, Bojesen A, Pedersen IS, Thomassen M, Jensen UB, Laitman Y, Rantala J, von Wachenfeldt A, Ehrencrona H, Askmalm MS, Borg Å, Kuchenbaecker KB, McGuffog L, Barrowdale D, Healey S, Lee A, Pharoah PD, Chenevix-Trench G, Antoniou AC, and Friedman E

Subjects
Adult, Cohort Studies, Female, Humans, Mutation, Polymorphism, Single Nucleotide, Retrospective Studies, Young Adult, Breast Neoplasms genetics, Genes, BRCA1 physiology, Genes, BRCA2 physiology, Ovarian Neoplasms genetics
Abstract

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes., Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach., Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments., Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers., Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies., (©2014 American Association for Cancer Research.)

Published
2015
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6. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

Author

Kuchenbaecker KB, Neuhausen SL, Robson M, Barrowdale D, McGuffog L, Mulligan AM, Andrulis IL, Spurdle AB, Schmidt MK, Schmutzler RK, Engel C, Wappenschmidt B, Nevanlinna H, Thomassen M, Southey M, Radice P, Ramus SJ, Domchek SM, Nathanson KL, Lee A, Healey S, Nussbaum RL, Rebbeck TR, Arun BK, James P, Karlan BY, Lester J, Cass I, Terry MB, Daly MB, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Steele L, v O Hansen T, Ejlertsen B, Gerdes AM, Nielsen FC, Dennis J, Cunningham J, Hart S, Slager S, Osorio A, Benitez J, Duran M, Weitzel JN, Tafur I, Hander M, Peterlongo P, Manoukian S, Peissel B, Roversi G, Scuvera G, Bonanni B, Mariani P, Volorio S, Dolcetti R, Varesco L, Papi L, Tibiletti MG, Giannini G, Fostira F, Konstantopoulou I, Garber J, Hamann U, Donaldson A, Brewer C, Foo C, Evans DG, Frost D, Eccles D, Douglas F, Brady A, Cook J, Tischkowitz M, Adlard J, Barwell J, Ong KR, Walker L, Izatt L, Side LE, Kennedy MJ, Rogers MT, Porteous ME, Morrison PJ, Platte R, Eeles R, Davidson R, Hodgson S, Ellis S, Godwin AK, Rhiem K, Meindl A, Ditsch N, Arnold N, Plendl H, Niederacher D, Sutter C, Steinemann D, Bogdanova-Markov N, Kast K, Varon-Mateeva R, Wang-Gohrke S, Gehrig A, Markiefka B, Buecher B, Lefol C, Stoppa-Lyonnet D, Rouleau E, Prieur F, Damiola F, Barjhoux L, Faivre L, Longy M, Sevenet N, Sinilnikova OM, Mazoyer S, Bonadona V, Caux-Moncoutier V, Isaacs C, Van Maerken T, Claes K, Piedmonte M, Andrews L, Hays J, Rodriguez GC, Caldes T, de la Hoya M, Khan S, Hogervorst FB, Aalfs CM, de Lange JL, Meijers-Heijboer HE, van der Hout AH, Wijnen JT, van Roozendaal KE, Mensenkamp AR, van den Ouweland AM, van Deurzen CH, van der Luijt RB, Olah E, Diez O, Lazaro C, Blanco I, Teulé A, Menendez M, Jakubowska A, Lubinski J, Cybulski C, Gronwald J, Jaworska-Bieniek K, Durda K, Arason A, Maugard C, Soucy P, Montagna M, Agata S, Teixeira MR, Olswold C, Lindor N, Pankratz VS, Hallberg E, Wang X, Szabo CI, Vijai J, Jacobs L, Corines M, Lincoln A, Berger A, Fink-Retter A, Singer CF, Rappaport C, Kaulich DG, Pfeiler G, Tea MK, Phelan CM, Mai PL, Greene MH, Rennert G, Imyanitov EN, Glendon G, Toland AE, Bojesen A, Pedersen IS, Jensen UB, Caligo MA, Friedman E, Berger R, Laitman Y, Rantala J, Arver B, Loman N, Borg A, Ehrencrona H, Olopade OI, Simard J, Easton DF, Chenevix-Trench G, Offit K, Couch FJ, and Antoniou AC

Subjects
Adult, Aged, Alleles, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma genetics, Carcinoma metabolism, Carcinoma pathology, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular metabolism, Carcinoma, Lobular pathology, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Carcinoma, Lobular genetics, Genes, BRCA1, Genes, BRCA2
Abstract

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers., Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement., Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement., Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Published
2014
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7. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

Author

Spurdle AB, Couch FJ, Parsons MT, McGuffog L, Barrowdale D, Bolla MK, Wang Q, Healey S, Schmutzler R, Wappenschmidt B, Rhiem K, Hahnen E, Engel C, Meindl A, Ditsch N, Arnold N, Plendl H, Niederacher D, Sutter C, Wang-Gohrke S, Steinemann D, Preisler-Adams S, Kast K, Varon-Mateeva R, Ellis S, Frost D, Platte R, Perkins J, Evans DG, Izatt L, Eeles R, Adlard J, Davidson R, Cole T, Scuvera G, Manoukian S, Bonanni B, Mariette F, Fortuzzi S, Viel A, Pasini B, Papi L, Varesco L, Balleine R, Nathanson KL, Domchek SM, Offitt K, Jakubowska A, Lindor N, Thomassen M, Jensen UB, Rantala J, Borg Å, Andrulis IL, Miron A, Hansen TV, Caldes T, Neuhausen SL, Toland AE, Nevanlinna H, Montagna M, Garber J, Godwin AK, Osorio A, Factor RE, Terry MB, Rebbeck TR, Karlan BY, Southey M, Rashid MU, Tung N, Pharoah PD, Blows FM, Dunning AM, Provenzano E, Hall P, Czene K, Schmidt MK, Broeks A, Cornelissen S, Verhoef S, Fasching PA, Beckmann MW, Ekici AB, Slamon DJ, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Chang-Claude J, Flesch-Janys D, Rudolph A, Seibold P, Aittomäki K, Muranen TA, Heikkilä P, Blomqvist C, Figueroa J, Chanock SJ, Brinton L, Lissowska J, Olson JE, Pankratz VS, John EM, Whittemore AS, West DW, Hamann U, Torres D, Ulmer HU, Rüdiger T, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, Eccles DM, Tapper WJ, Durcan L, Jones L, Peto J, dos-Santos-Silva I, Fletcher O, Johnson N, Dwek M, Swann R, Bane AL, Glendon G, Mulligan AM, Giles GG, Milne RL, Baglietto L, McLean C, Carpenter J, Clarke C, Scott R, Brauch H, Brüning T, Ko YD, Cox A, Cross SS, Reed MW, Lubinski J, Jaworska-Bieniek K, Durda K, Gronwald J, Dörk T, Bogdanova N, Park-Simon TW, Hillemanns P, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Burwinkel B, Marme F, Surovy H, Yang R, Anton-Culver H, Ziogas A, Hooning MJ, Collée JM, Martens JW, Tilanus-Linthorst MM, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Lindblom A, Margolin S, Joseph V, Robson M, Rau-Murthy R, González-Neira A, Arias JI, Zamora P, Benítez J, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Peterlongo P, Zaffaroni D, Barile M, Capra F, Radice P, Teo SH, Easton DF, Antoniou AC, Chenevix-Trench G, and Goldgar DE

Subjects
Adult, Age Factors, Aged, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma metabolism, Carcinoma pathology, Female, Humans, Likelihood Functions, Middle Aged, Mutation, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Breast Neoplasms genetics, Carcinoma genetics, Genes, BRCA1, Genes, BRCA2, Triple Negative Breast Neoplasms genetics
Abstract

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling., Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach., Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24))., Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Published
2014
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8. Lymphocyte telomere length is long in BRCA1 and BRCA2 mutation carriers regardless of cancer-affected status.

Author

Pooley KA, McGuffog L, Barrowdale D, Frost D, Ellis SD, Fineberg E, Platte R, Izatt L, Adlard J, Bardwell J, Brewer C, Cole T, Cook J, Davidson R, Donaldson A, Dorkins H, Douglas F, Eason J, Houghton C, Kennedy MJ, McCann E, Miedzybrodzka Z, Murray A, Porteous ME, Rogers MT, Side LE, Tischkowitz M, Walker L, Hodgson S, Eccles DM, Morrison PJ, Evans DG, Eeles RA, Antoniou AC, Easton DF, and Dunning AM

Subjects
Female, Humans, Lymphocytes, Male, Mutation, Breast Neoplasms genetics, Genes, BRCA1 physiology, Genes, BRCA2 physiology, Telomere genetics
Abstract

Background: Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian, and other cancer types., Methods: We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput quantitative PCR. Participants were from the EMBRACE study in United Kingdom and Eire (n = 4,822) and comprised BRCA1 (n = 1,628) and BRCA2 (n = 1,506) mutation carriers and their non-carrier relatives (n = 1,688)., Results: We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, Ptrend = 0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, Ptrend = 0.0016)., Conclusions: Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it seems that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers., Impact: The finding that mutation carriers have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length in BRCA mutation carriers and their relatives. The null cancer-risk association supports recent large prospective studies of breast and ovarian cancer and indicates that mean telomere length would not be a useful biomarker in these cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1018-24. ©2014 AACR., (©2014 American Association for Cancer Research.)

Published
2014
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9. A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.

Author

Barnett GC, Thompson D, Fachal L, Kerns S, Talbot C, Elliott RM, Dorling L, Coles CE, Dearnaley DP, Rosenstein BS, Vega A, Symonds P, Yarnold J, Baynes C, Michailidou K, Dennis J, Tyrer JP, Wilkinson JS, Gómez-Caamaño A, Tanteles GA, Platte R, Mayes R, Conroy D, Maranian M, Luccarini C, Gulliford SL, Sydes MR, Hall E, Haviland J, Misra V, Titley J, Bentzen SM, Pharoah PD, Burnet NG, Dunning AM, and West CM

Subjects
Dose-Response Relationship, Radiation, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Prospective Studies, Radiotherapy, Adjuvant adverse effects, Breast Neoplasms genetics, Breast Neoplasms radiotherapy, Genetic Variation, Prostatic Neoplasms genetics, Prostatic Neoplasms radiotherapy, Radiation Injuries genetics, Radiotherapy, Intensity-Modulated adverse effects
Abstract

Background and Purpose: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy., Materials and Methods: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer., Results: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts., Conclusions: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Published
2014
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10. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Osorio A, Milne RL, Kuchenbaecker K, Vaclová T, Pita G, Alonso R, Peterlongo P, Blanco I, de la Hoya M, Duran M, Díez O, Ramón Y Cajal T, Konstantopoulou I, Martínez-Bouzas C, Andrés Conejero R, Soucy P, McGuffog L, Barrowdale D, Lee A, Arver B, Rantala J, Loman N, Ehrencrona H, Olopade OI, Beattie MS, Domchek SM, Nathanson K, Rebbeck TR, Arun BK, Karlan BY, Walsh C, Lester J, John EM, Whittemore AS, Daly MB, Southey M, Hopper J, Terry MB, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Hansen TV, Jønson L, Ejlertsen B, Gerdes AM, Infante M, Herráez B, Moreno LT, Weitzel JN, Herzog J, Weeman K, Manoukian S, Peissel B, Zaffaroni D, Scuvera G, Bonanni B, Mariette F, Volorio S, Viel A, Varesco L, Papi L, Ottini L, Tibiletti MG, Radice P, Yannoukakos D, Garber J, Ellis S, Frost D, Platte R, Fineberg E, Evans G, Lalloo F, Izatt L, Eeles R, Adlard J, Davidson R, Cole T, Eccles D, Cook J, Hodgson S, Brewer C, Tischkowitz M, Douglas F, Porteous M, Side L, Walker L, Morrison P, Donaldson A, Kennedy J, Foo C, Godwin AK, Schmutzler RK, Wappenschmidt B, Rhiem K, Engel C, Meindl A, Ditsch N, Arnold N, Plendl HJ, Niederacher D, Sutter C, Wang-Gohrke S, Steinemann D, Preisler-Adams S, Kast K, Varon-Mateeva R, Gehrig A, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Damiola F, Poppe B, Claes K, Piedmonte M, Tucker K, Backes F, Rodríguez G, Brewster W, Wakeley K, Rutherford T, Caldés T, Nevanlinna H, Aittomäki K, Rookus MA, van Os TA, van der Kolk L, de Lange JL, Meijers-Heijboer HE, van der Hout AH, van Asperen CJ, Gómez Garcia EB, Hoogerbrugge N, Collée JM, van Deurzen CH, van der Luijt RB, Devilee P, Olah E, Lázaro C, Teulé A, Menéndez M, Jakubowska A, Cybulski C, Gronwald J, Lubinski J, Durda K, Jaworska-Bieniek K, Johannsson OT, Maugard C, Montagna M, Tognazzo S, Teixeira MR, Healey S, Olswold C, Guidugli L, Lindor N, Slager S, Szabo CI, Vijai J, Robson M, Kauff N, Zhang L, Rau-Murthy R, Fink-Retter A, Singer CF, Rappaport C, Geschwantler Kaulich D, Pfeiler G, Tea MK, Berger A, Phelan CM, Greene MH, Mai PL, Lejbkowicz F, Andrulis I, Mulligan AM, Glendon G, Toland AE, Bojesen A, Pedersen IS, Sunde L, Thomassen M, Kruse TA, Jensen UB, Friedman E, Laitman Y, Shimon SP, Simard J, Easton DF, Offit K, Couch FJ, Chenevix-Trench G, Antoniou AC, and Benitez J

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Female, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Risk, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, DNA Glycosylases genetics, DNA Repair genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide genetics
Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Published
2014
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11. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE.

Author

Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, Evans DG, Izatt L, Eeles RA, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Tischkowitz M, Douglas F, Hodgson S, Walker L, Porteous ME, Morrison PJ, Side LE, Kennedy MJ, Houghton C, Donaldson A, Rogers MT, Dorkins H, Miedzybrodzka Z, Gregory H, Eason J, Barwell J, McCann E, Murray A, Antoniou AC, and Easton DF

Subjects
Adult, Aged, Confounding Factors, Epidemiologic, Female, Genetic Predisposition to Disease, Humans, Incidence, Ireland epidemiology, Kaplan-Meier Estimate, Middle Aged, Odds Ratio, Ovarian Neoplasms prevention & control, Ovariectomy, Primary Prevention methods, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Salpingectomy, Surveys and Questionnaires, United Kingdom epidemiology, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Heterozygote, Mutation, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Background: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles., Methods: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided., Results: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02)., Conclusions: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

Published
2013
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12. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Author

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, Lawrenson K, Stutz MD, Lu Y, Karevan R, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, Rossing MA, Pita G, Doherty JA, Alvarez N, Larson MC, Fridley BL, Schoof N, Chang-Claude J, Cicek MS, Peto J, Kalli KR, Broeks A, Armasu SM, Schmidt MK, Braaf LM, Winterhoff B, Nevanlinna H, Konecny GE, Lambrechts D, Rogmann L, Guénel P, Teoman A, Milne RL, Garcia JJ, Cox A, Shridhar V, Burwinkel B, Marme F, Hein R, Sawyer EJ, Haiman CA, Wang-Gohrke S, Andrulis IL, Moysich KB, Hopper JL, Odunsi K, Lindblom A, Giles GG, Brenner H, Simard J, Lurie G, Fasching PA, Carney ME, Radice P, Wilkens LR, Swerdlow A, Goodman MT, Brauch H, Garcia-Closas M, Hillemanns P, Winqvist R, Dürst M, Devilee P, Runnebaum I, Jakubowska A, Lubinski J, Mannermaa A, Butzow R, Bogdanova NV, Dörk T, Pelttari LM, Zheng W, Leminen A, Anton-Culver H, Bunker CH, Kristensen V, Ness RB, Muir K, Edwards R, Meindl A, Heitz F, Matsuo K, du Bois A, Wu AH, Harter P, Teo SH, Schwaab I, Shu XO, Blot W, Hosono S, Kang D, Nakanishi T, Hartman M, Yatabe Y, Hamann U, Karlan BY, Sangrajrang S, Kjaer SK, Gaborieau V, Jensen A, Eccles D, Høgdall E, Shen CY, Brown J, Woo YL, Shah M, Azmi MA, Luben R, Omar SZ, Czene K, Vierkant RA, Nordestgaard BG, Flyger H, Vachon C, Olson JE, Wang X, Levine DA, Rudolph A, Weber RP, Flesch-Janys D, Iversen E, Nickels S, Schildkraut JM, Silva Idos S, Cramer DW, Gibson L, Terry KL, Fletcher O, Vitonis AF, van der Schoot CE, Poole EM, Hogervorst FB, Tworoger SS, Liu J, Bandera EV, Li J, Olson SH, Humphreys K, Orlow I, Blomqvist C, Rodriguez-Rodriguez L, Aittomäki K, Salvesen HB, Muranen TA, Wik E, Brouwers B, Krakstad C, Wauters E, Halle MK, Wildiers H, Kiemeney LA, Mulot C, Aben KK, Laurent-Puig P, Altena AM, Truong T, Massuger LF, Benitez J, Pejovic T, Perez JI, Hoatlin M, Zamora MP, Cook LS, Balasubramanian SP, Kelemen LE, Schneeweiss A, Le ND, Sohn C, Brooks-Wilson A, Tomlinson I, Kerin MJ, Miller N, Cybulski C, Henderson BE, Menkiszak J, Schumacher F, Wentzensen N, Le Marchand L, Yang HP, Mulligan AM, Glendon G, Engelholm SA, Knight JA, Høgdall CK, Apicella C, Gore M, Tsimiklis H, Song H, Southey MC, Jager A, den Ouweland AM, Brown R, Martens JW, Flanagan JM, Kriege M, Paul J, Margolin S, Siddiqui N, Severi G, Whittemore AS, Baglietto L, McGuire V, Stegmaier C, Sieh W, Müller H, Arndt V, Labrèche F, Gao YT, Goldberg MS, Yang G, Dumont M, McLaughlin JR, Hartmann A, Ekici AB, Beckmann MW, Phelan CM, Lux MP, Permuth-Wey J, Peissel B, Sellers TA, Ficarazzi F, Barile M, Ziogas A, Ashworth A, Gentry-Maharaj A, Jones M, Ramus SJ, Orr N, Menon U, Pearce CL, Brüning T, Pike MC, Ko YD, Lissowska J, Figueroa J, Kupryjanczyk J, Chanock SJ, Dansonka-Mieszkowska A, Jukkola-Vuorinen A, Rzepecka IK, Pylkäs K, Bidzinski M, Kauppila S, Hollestelle A, Seynaeve C, Tollenaar RA, Durda K, Jaworska K, Hartikainen JM, Kosma VM, Kataja V, Antonenkova NN, Long J, Shrubsole M, Deming-Halverson S, Lophatananon A, Siriwanarangsan P, Stewart-Brown S, Ditsch N, Lichtner P, Schmutzler RK, Ito H, Iwata H, Tajima K, Tseng CC, Stram DO, van den Berg D, Yip CH, Ikram MK, Teh YC, Cai H, Lu W, Signorello LB, Cai Q, Noh DY, Yoo KY, Miao H, Iau PT, Teo YY, McKay J, Shapiro C, Ademuyiwa F, Fountzilas G, Hsiung CN, Yu JC, Hou MF, Healey CS, Luccarini C, Peock S, Stoppa-Lyonnet D, Peterlongo P, Rebbeck TR, Piedmonte M, Singer CF, Friedman E, Thomassen M, Offit K, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Garber J, Narod SA, Weitzel JN, Montagna M, Olah E, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Imyanitov EN, Tihomirova L, Arun BK, Campbell I, Mensenkamp AR, van Asperen CJ, van Roozendaal KE, Meijers-Heijboer H, Collée JM, Oosterwijk JC, Hooning MJ, Rookus MA, van der Luijt RB, Os TA, Evans DG, Frost D, Fineberg E, Barwell J, Walker L, Kennedy MJ, Platte R, Davidson R, Ellis SD, Cole T, Bressac-de Paillerets B, Buecher B, Damiola F, Faivre L, Frenay M, Sinilnikova OM, Caron O, Giraud S, Mazoyer S, Bonadona V, Caux-Moncoutier V, Toloczko-Grabarek A, Gronwald J, Byrski T, Spurdle AB, Bonanni B, Zaffaroni D, Giannini G, Bernard L, Dolcetti R, Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea MK, Paluch SS, Laitman Y, Skytte AB, Kruse TA, Jensen UB, Robson M, Gerdes AM, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro AN, Gayther SA, Pharoah PD, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, and Dunning AM

Subjects
Alternative Splicing, Breast Neoplasms pathology, Case-Control Studies, Chromatin genetics, DNA Methylation, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases metabolism, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms etiology, Genetic Loci genetics, Ovarian Neoplasms etiology, Polymorphism, Single Nucleotide genetics, Telomerase genetics, Telomere genetics
Abstract

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Published
2013
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13. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Author

Gaudet MM, Kuchenbaecker KB, Vijai J, Klein RJ, Kirchhoff T, McGuffog L, Barrowdale D, Dunning AM, Lee A, Dennis J, Healey S, Dicks E, Soucy P, Sinilnikova OM, Pankratz VS, Wang X, Eldridge RC, Tessier DC, Vincent D, Bacot F, Hogervorst FB, Peock S, Stoppa-Lyonnet D, Peterlongo P, Schmutzler RK, Nathanson KL, Piedmonte M, Singer CF, Thomassen M, Hansen Tv, Neuhausen SL, Blanco I, Greene MH, Garber J, Weitzel JN, Andrulis IL, Goldgar DE, D'Andrea E, Caldes T, Nevanlinna H, Osorio A, van Rensburg EJ, Arason A, Rennert G, van den Ouweland AM, van der Hout AH, Kets CM, Aalfs CM, Wijnen JT, Ausems MG, Frost D, Ellis S, Fineberg E, Platte R, Evans DG, Jacobs C, Adlard J, Tischkowitz M, Porteous ME, Damiola F, Golmard L, Barjhoux L, Longy M, Belotti M, Ferrer SF, Mazoyer S, Spurdle AB, Manoukian S, Barile M, Genuardi M, Arnold N, Meindl A, Sutter C, Wappenschmidt B, Domchek SM, Pfeiler G, Friedman E, Jensen UB, Robson M, Shah S, Lazaro C, Mai PL, Benitez J, Southey MC, Schmidt MK, Fasching PA, Peto J, Humphreys MK, Wang Q, Michailidou K, Sawyer EJ, Burwinkel B, Guénel P, Bojesen SE, Milne RL, Brenner H, Lochmann M, Aittomäki K, Dörk T, Margolin S, Mannermaa A, Lambrechts D, Chang-Claude J, Radice P, Giles GG, Haiman CA, Winqvist R, Devillee P, García-Closas M, Schoof N, Hooning MJ, Cox A, Pharoah PD, Jakubowska A, Orr N, González-Neira A, Pita G, Alonso MR, Hall P, Couch FJ, Simard J, Altshuler D, Easton DF, Chenevix-Trench G, Antoniou AC, and Offit K

Subjects
Adult, Aged, Alleles, BRCA1 Protein genetics, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Risk Factors, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 6 genetics, Genome-Wide Association Study
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Published
2013
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14. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

Author

Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, Soucy P, Fredericksen Z, Barrowdale D, Dennis J, Gaudet MM, Dicks E, Kosel M, Healey S, Sinilnikova OM, Lee A, Bacot F, Vincent D, Hogervorst FB, Peock S, Stoppa-Lyonnet D, Jakubowska A, Radice P, Schmutzler RK, Domchek SM, Piedmonte M, Singer CF, Friedman E, Thomassen M, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Greene MH, Karlan BY, Garber J, Phelan CM, Weitzel JN, Montagna M, Olah E, Andrulis IL, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Nevanlinna H, Osorio A, Terry MB, Daly MB, van Rensburg EJ, Hamann U, Ramus SJ, Toland AE, Caligo MA, Olopade OI, Tung N, Claes K, Beattie MS, Southey MC, Imyanitov EN, Tischkowitz M, Janavicius R, John EM, Kwong A, Diez O, Balmaña J, Barkardottir RB, Arun BK, Rennert G, Teo SH, Ganz PA, Campbell I, van der Hout AH, van Deurzen CH, Seynaeve C, Gómez Garcia EB, van Leeuwen FE, Meijers-Heijboer HE, Gille JJ, Ausems MG, Blok MJ, Ligtenberg MJ, Rookus MA, Devilee P, Verhoef S, van Os TA, Wijnen JT, Frost D, Ellis S, Fineberg E, Platte R, Evans DG, Izatt L, Eeles RA, Adlard J, Eccles DM, Cook J, Brewer C, Douglas F, Hodgson S, Morrison PJ, Side LE, Donaldson A, Houghton C, Rogers MT, Dorkins H, Eason J, Gregory H, McCann E, Murray A, Calender A, Hardouin A, Berthet P, Delnatte C, Nogues C, Lasset C, Houdayer C, Leroux D, Rouleau E, Prieur F, Damiola F, Sobol H, Coupier I, Venat-Bouvet L, Castera L, Gauthier-Villars M, Léoné M, Pujol P, Mazoyer S, Bignon YJ, Złowocka-Perłowska E, Gronwald J, Lubinski J, Durda K, Jaworska K, Huzarski T, Spurdle AB, Viel A, Peissel B, Bonanni B, Melloni G, Ottini L, Papi L, Varesco L, Tibiletti MG, Peterlongo P, Volorio S, Manoukian S, Pensotti V, Arnold N, Engel C, Deissler H, Gadzicki D, Gehrig A, Kast K, Rhiem K, Meindl A, Niederacher D, Ditsch N, Plendl H, Preisler-Adams S, Engert S, Sutter C, Varon-Mateeva R, Wappenschmidt B, Weber BH, Arver B, Stenmark-Askmalm M, Loman N, Rosenquist R, Einbeigi Z, Nathanson KL, Rebbeck TR, Blank SV, Cohn DE, Rodriguez GC, Small L, Friedlander M, Bae-Jump VL, Fink-Retter A, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Lindor NM, Kaufman B, Shimon Paluch S, Laitman Y, Skytte AB, Gerdes AM, Pedersen IS, Moeller ST, Kruse TA, Jensen UB, Vijai J, Sarrel K, Robson M, Kauff N, Mulligan AM, Glendon G, Ozcelik H, Ejlertsen B, Nielsen FC, Jønson L, Andersen MK, Ding YC, Steele L, Foretova L, Teulé A, Lazaro C, Brunet J, Pujana MA, Mai PL, Loud JT, Walsh C, Lester J, Orsulic S, Narod SA, Herzog J, Sand SR, Tognazzo S, Agata S, Vaszko T, Weaver J, Stavropoulou AV, Buys SS, Romero A, de la Hoya M, Aittomäki K, Muranen TA, Duran M, Chung WK, Lasa A, Dorfling CM, Miron A, Benitez J, Senter L, Huo D, Chan SB, Sokolenko AP, Chiquette J, Tihomirova L, Friebel TM, Agnarsson BA, Lu KH, Lejbkowicz F, James PA, Hall P, Dunning AM, Tessier D, Cunningham J, Slager SL, Wang C, Hart S, Stevens K, Simard J, Pastinen T, Pankratz VS, Offit K, Easton DF, Chenevix-Trench G, and Antoniou AC

Subjects
BRCA2 Protein genetics, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, BRCA1 Protein genetics, Breast Neoplasms genetics, Genome-Wide Association Study, Ovarian Neoplasms genetics
Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Competing Interests: The authors have declared that no competing interests exist.

Published
2013
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15. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.

Author

Ding YC, McGuffog L, Healey S, Friedman E, Laitman Y, Paluch-Shimon S, Kaufman B, Liljegren A, Lindblom A, Olsson H, Kristoffersson U, Stenmark-Askmalm M, Melin B, Domchek SM, Nathanson KL, Rebbeck TR, Jakubowska A, Lubinski J, Jaworska K, Durda K, Gronwald J, Huzarski T, Cybulski C, Byrski T, Osorio A, Cajal TR, Stavropoulou AV, Benítez J, Hamann U, Rookus M, Aalfs CM, de Lange JL, Meijers-Heijboer HE, Oosterwijk JC, van Asperen CJ, Gómez García EB, Hoogerbrugge N, Jager A, van der Luijt RB, Easton DF, Peock S, Frost D, Ellis SD, Platte R, Fineberg E, Evans DG, Lalloo F, Izatt L, Eeles R, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Tischkowitz M, Godwin AK, Pathak H, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Barjhoux L, Léoné M, Gauthier-Villars M, Caux-Moncoutier V, de Pauw A, Hardouin A, Berthet P, Dreyfus H, Ferrer SF, Collonge-Rame MA, Sokolowska J, Buys S, Daly M, Miron A, Terry MB, Chung W, John EM, Southey M, Goldgar D, Singer CF, Tea MK, Gschwantler-Kaulich D, Fink-Retter A, Hansen TV, Ejlertsen B, Johannsson OT, Offit K, Sarrel K, Gaudet MM, Vijai J, Robson M, Piedmonte MR, Andrews L, Cohn D, DeMars LR, DiSilvestro P, Rodriguez G, Toland AE, Montagna M, Agata S, Imyanitov E, Isaacs C, Janavicius R, Lazaro C, Blanco I, Ramus SJ, Sucheston L, Karlan BY, Gross J, Ganz PA, Beattie MS, Schmutzler RK, Wappenschmidt B, Meindl A, Arnold N, Niederacher D, Preisler-Adams S, Gadzicki D, Varon-Mateeva R, Deissler H, Gehrig A, Sutter C, Kast K, Nevanlinna H, Aittomäki K, Simard J, Spurdle AB, Beesley J, Chen X, Tomlinson GE, Weitzel J, Garber JE, Olopade OI, Rubinstein WS, Tung N, Blum JL, Narod SA, Brummel S, Gillen DL, Lindor N, Fredericksen Z, Pankratz VS, Couch FJ, Radice P, Peterlongo P, Greene MH, Loud JT, Mai PL, Andrulis IL, Glendon G, Ozcelik H, Gerdes AM, Thomassen M, Jensen UB, Skytte AB, Caligo MA, Lee A, Chenevix-Trench G, Antoniou AC, and Neuhausen SL

Subjects
Cohort Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Mutation, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Insulin Receptor Substrate Proteins genetics, Ovarian Neoplasms genetics
Abstract

Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers., Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers., Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03)., Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers., Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers., (©2012 AACR.)

Published
2012
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16. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Couch FJ, Gaudet MM, Antoniou AC, Ramus SJ, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, Wang X, Kirchhoff T, McGuffog L, Barrowdale D, Lee A, Healey S, Sinilnikova OM, Andrulis IL, Ozcelik H, Mulligan AM, Thomassen M, Gerdes AM, Jensen UB, Skytte AB, Kruse TA, Caligo MA, von Wachenfeldt A, Barbany-Bustinza G, Loman N, Soller M, Ehrencrona H, Karlsson P, Nathanson KL, Rebbeck TR, Domchek SM, Jakubowska A, Lubinski J, Jaworska K, Durda K, Zlowocka E, Huzarski T, Byrski T, Gronwald J, Cybulski C, Górski B, Osorio A, Durán M, Tejada MI, Benitez J, Hamann U, Hogervorst FB, van Os TA, van Leeuwen FE, Meijers-Heijboer HE, Wijnen J, Blok MJ, Kets M, Hooning MJ, Oldenburg RA, Ausems MG, Peock S, Frost D, Ellis SD, Platte R, Fineberg E, Evans DG, Jacobs C, Eeles RA, Adlard J, Davidson R, Eccles DM, Cole T, Cook J, Paterson J, Brewer C, Douglas F, Hodgson SV, Morrison PJ, Walker L, Porteous ME, Kennedy MJ, Side LE, Bove B, Godwin AK, Stoppa-Lyonnet D, Fassy-Colcombet M, Castera L, Cornelis F, Mazoyer S, Léoné M, Boutry-Kryza N, Bressac-de Paillerets B, Caron O, Pujol P, Coupier I, Delnatte C, Akloul L, Lynch HT, Snyder CL, Buys SS, Daly MB, Terry M, Chung WK, John EM, Miron A, Southey MC, Hopper JL, Goldgar DE, Singer CF, Rappaport C, Tea MK, Fink-Retter A, Hansen TV, Nielsen FC, Arason A, Vijai J, Shah S, Sarrel K, Robson ME, Piedmonte M, Phillips K, Basil J, Rubinstein WS, Boggess J, Wakeley K, Ewart-Toland A, Montagna M, Agata S, Imyanitov EN, Isaacs C, Janavicius R, Lazaro C, Blanco I, Feliubadalo L, Brunet J, Gayther SA, Pharoah PP, Odunsi KO, Karlan BY, Walsh CS, Olah E, Teo SH, Ganz PA, Beattie MS, van Rensburg EJ, Dorfling CM, Diez O, Kwong A, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Ditsch N, Arnold N, Heidemann S, Niederacher D, Preisler-Adams S, Gadzicki D, Varon-Mateeva R, Deissler H, Gehrig A, Sutter C, Kast K, Fiebig B, Heinritz W, Caldes T, de la Hoya M, Muranen TA, Nevanlinna H, Tischkowitz MD, Spurdle AB, Neuhausen SL, Ding YC, Lindor NM, Fredericksen Z, Pankratz VS, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Barile M, Bernard L, Viel A, Giannini G, Varesco L, Radice P, Greene MH, Mai PL, Easton DF, Chenevix-Trench G, Offit K, and Simard J

Subjects
Adult, Aged, Breast Neoplasms epidemiology, Breast Neoplasms metabolism, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Immunoenzyme Techniques, Middle Aged, Mutation genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms metabolism, Polymorphism, Single Nucleotide genetics, Prognosis, Risk Factors, United States epidemiology, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 19 genetics, DNA-Binding Proteins genetics, Ovarian Neoplasms genetics, Receptors, Estrogen metabolism, Transcription Factors genetics
Abstract

Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)., Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined., Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3))., Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers., Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers., (©2012 AACR.)

Published
2012
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17. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study.

Author

Barnett GC, Coles CE, Elliott RM, Baynes C, Luccarini C, Conroy D, Wilkinson JS, Tyrer J, Misra V, Platte R, Gulliford SL, Sydes MR, Hall E, Bentzen SM, Dearnaley DP, Burnet NG, Pharoah PD, Dunning AM, and West CM

Subjects
Dose-Response Relationship, Radiation, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Linear Models, Male, Odds Ratio, Prospective Studies, Radiation Injuries pathology, Radiotherapy, Adjuvant adverse effects, Risk Assessment, Risk Factors, Time Factors, United Kingdom, Breast Neoplasms genetics, Breast Neoplasms radiotherapy, Dose Fractionation, Radiation, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics, Prostatic Neoplasms radiotherapy, Radiation Injuries genetics, Radiotherapy, Intensity-Modulated adverse effects
Abstract

Background: Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset., Methods: 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2., Findings: None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance., Interpretation: We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed., Funding: Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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18. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.

Author

Figueroa JD, Garcia-Closas M, Humphreys M, Platte R, Hopper JL, Southey MC, Apicella C, Hammet F, Schmidt MK, Broeks A, Tollenaar RA, Van't Veer LJ, Fasching PA, Beckmann MW, Ekici AB, Strick R, Peto J, dos Santos Silva I, Fletcher O, Johnson N, Sawyer E, Tomlinson I, Kerin M, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Bojesen S, Flyger H, Nordestgaard BG, Benítez J, Milne RL, Ignacio Arias J, Zamora MP, Brenner H, Müller H, Arndt V, Rahman N, Turnbull C, Seal S, Renwick A, Brauch H, Justenhoven C, Brüning T, Chang-Claude J, Hein R, Wang-Gohrke S, Dörk T, Schürmann P, Bremer M, Hillemanns P, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Bogdanova N, Antonenkova N, Rogov YI, Karstens JH, Bermisheva M, Prokofieva D, Gantcev SH, Khusnutdinova E, Lindblom A, Margolin S, Chenevix-Trench G, Beesley J, Chen X, Mannermaa A, Kosma VM, Soini Y, Kataja V, Lambrechts D, Yesilyurt BT, Chrisiaens MR, Peeters S, Radice P, Peterlongo P, Manoukian S, Barile M, Couch F, Lee AM, Diasio R, Wang X, Giles GG, Severi G, Baglietto L, Maclean C, Offit K, Robson M, Joseph V, Gaudet M, John EM, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis I, Knight JA, Mulligan AM, O'Malley FP, Brinton LA, Sherman ME, Lissowska J, Chanock SJ, Hooning M, Martens JW, van den Ouweland AM, Collée JM, Hall P, Czene K, Cox A, Brock IW, Reed MW, Cross SS, Pharoah P, Dunning AM, Kang D, Yoo KY, Noh DY, Ahn SH, Jakubowska A, Lubinski J, Jaworska K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Shen CY, Ding SL, Hsu HM, Yu JC, Anton-Culver H, Ziogas A, Ashworth A, Swerdlow A, Jones M, Orr N, Trentham-Dietz A, Egan K, Newcomb P, Titus-Ernstoff L, Easton D, and Spurdle AB

Subjects
Alleles, Case-Control Studies, Confidence Intervals, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Humans, Odds Ratio, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Risk Factors, Breast Neoplasms classification, Breast Neoplasms genetics, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 14 genetics, DNA-Binding Proteins genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
Abstract

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

Published
2011
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19. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Author

Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L, Healey S, Lee A, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Cattaneo E, Barile M, Pensotti V, Pasini B, Dolcetti R, Giannini G, Putignano AL, Varesco L, Radice P, Mai PL, Greene MH, Andrulis IL, Glendon G, Ozcelik H, Thomassen M, Gerdes AM, Kruse TA, Birk Jensen U, Crüger DG, Caligo MA, Laitman Y, Milgrom R, Kaufman B, Paluch-Shimon S, Friedman E, Loman N, Harbst K, Lindblom A, Arver B, Ehrencrona H, Melin B, Nathanson KL, Domchek SM, Rebbeck T, Jakubowska A, Lubinski J, Gronwald J, Huzarski T, Byrski T, Cybulski C, Gorski B, Osorio A, Ramón y Cajal T, Fostira F, Andrés R, Benitez J, Hamann U, Hogervorst FB, Rookus MA, Hooning MJ, Nelen MR, van der Luijt RB, van Os TA, van Asperen CJ, Devilee P, Meijers-Heijboer HE, Gómez Garcia EB, Peock S, Cook M, Frost D, Platte R, Leyland J, Evans DG, Lalloo F, Eeles R, Izatt L, Adlard J, Davidson R, Eccles D, Ong KR, Cook J, Douglas F, Paterson J, Kennedy MJ, Miedzybrodzka Z, Godwin A, Stoppa-Lyonnet D, Buecher B, Belotti M, Tirapo C, Mazoyer S, Barjhoux L, Lasset C, Leroux D, Faivre L, Bronner M, Prieur F, Nogues C, Rouleau E, Pujol P, Coupier I, Frénay M, Hopper JL, Daly MB, Terry MB, John EM, Buys SS, Yassin Y, Miron A, Goldgar D, Singer CF, Tea MK, Pfeiler G, Dressler AC, Hansen Tv, Jønson L, Ejlertsen B, Barkardottir RB, Kirchhoff T, Offit K, Piedmonte M, Rodriguez G, Small L, Boggess J, Blank S, Basil J, Azodi M, Toland AE, Montagna M, Tognazzo S, Agata S, Imyanitov E, Janavicius R, Lazaro C, Blanco I, Pharoah PD, Sucheston L, Karlan BY, Walsh CS, Olah E, Bozsik A, Teo SH, Seldon JL, Beattie MS, van Rensburg EJ, Sluiter MD, Diez O, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Ruehl I, Varon-Mateeva R, Kast K, Deissler H, Niederacher D, Arnold N, Gadzicki D, Schönbuchner I, Caldes T, de la Hoya M, Nevanlinna H, Aittomäki K, Dumont M, Chiquette J, Tischkowitz M, Chen X, Beesley J, Spurdle AB, Neuhausen SL, Chun Ding Y, Fredericksen Z, Wang X, Pankratz VS, Couch F, Simard J, Easton DF, and Chenevix-Trench G

Subjects
Adult, Aged, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 6 genetics, Female, Heterozygote, Humans, Middle Aged, Polymorphism, Single Nucleotide genetics, Risk Factors, Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human genetics, Genetic Predisposition to Disease, Mutation genetics
Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Published
2011
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20. CYP2D6 gene variants and their association with breast cancer susceptibility.

Author

Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Earl HM, Dunning AM, Pharoah PD, and Caldas C

Subjects
Breast metabolism, Breast pathology, Case-Control Studies, DNA, Neoplasm genetics, Female, Genotype, Humans, Polymerase Chain Reaction, Prognosis, Risk Factors, Breast Neoplasms genetics, Cytochrome P-450 CYP2D6 genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics
Abstract

Background: The gene encoding the phase I enzyme cytochrome P4502D6 (CYP2D6) has been previously investigated for its potential predictive role in the efficacy of breast cancer treatments such as tamoxifen, but its role in breast cancer susceptibility is unclear. This study aims to evaluate the association between germ line variations in CYP2D6 and breast cancer susceptibility., Methods: DNA samples from 13,472 cases and controls were genotyped for seven known functional variants [minor allele frequency (MAF) ≥ 0.01] and five single nucleotide polymorphisms (SNP) that tag common genetic variation (MAF > 0.05) in CYP2D6., Results: One relatively rare functional variant, CYP2D6*6, (MAF = 0.01) showed a modest increased association with breast cancer susceptibility (P(trend) = 0.02; OR = 1.32; 95% CI = 1.04-1.68). All other functional and tagSNPs showed no association with breast cancer susceptibility., Conclusions: Common variants of CYP2D6 do not play a significant role in breast cancer susceptibility. However, this study raises questions regarding the role of rare variants, such as CYP2D6*6, in breast cancer susceptibility which merit further investigation., Impact: This large case-control study, involving 13,472 women, found no evidence of any association between common CYP2D6 gene variants and breast cancer susceptibility. However, one relatively rare functional variant CYP2D6*6 showed a modest association with breast cancer susceptibility, indicating that the role of rare CYP2D6 variants in breast cancer risk is unclear and requires further investigation in an adequately powered study., (©2011 AACR.)

Published
2011
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21. Exploring the link between MORF4L1 and risk of breast cancer.

Author

Martrat G, Maxwell CM, Tominaga E, Porta-de-la-Riva M, Bonifaci N, Gómez-Baldó L, Bogliolo M, Lázaro C, Blanco I, Brunet J, Aguilar H, Fernández-Rodríguez J, Seal S, Renwick A, Rahman N, Kühl J, Neveling K, Schindler D, Ramírez MJ, Castellà M, Hernández G, Easton DF, Peock S, Cook M, Oliver CT, Frost D, Platte R, Evans DG, Lalloo F, Eeles R, Izatt L, Chu C, Davidson R, Ong KR, Cook J, Douglas F, Hodgson S, Brewer C, Morrison PJ, Porteous M, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Roversi G, Barile M, Viel A, Pasini B, Ottini L, Putignano AL, Savarese A, Bernard L, Radice P, Healey S, Spurdle A, Chen X, Beesley J, Rookus MA, Verhoef S, Tilanus-Linthorst MA, Vreeswijk MP, Asperen CJ, Bodmer D, Ausems MG, van Os TA, Blok MJ, Meijers-Heijboer HE, Hogervorst FB, Goldgar DE, Buys S, John EM, Miron A, Southey M, Daly MB, Harbst K, Borg A, Rantala J, Barbany-Bustinza G, Ehrencrona H, Stenmark-Askmalm M, Kaufman B, Laitman Y, Milgrom R, Friedman E, Domchek SM, Nathanson KL, Rebbeck TR, Johannsson OT, Couch FJ, Wang X, Fredericksen Z, Cuadras D, Moreno V, Pientka FK, Depping R, Caldés T, Osorio A, Benítez J, Bueren J, Heikkinen T, Nevanlinna H, Hamann U, Torres D, Caligo MA, Godwin AK, Imyanitov EN, Janavicius R, Sinilnikova OM, Stoppa-Lyonnet D, Mazoyer S, Verny-Pierre C, Castera L, de Pauw A, Bignon YJ, Uhrhammer N, Peyrat JP, Vennin P, Ferrer SF, Collonge-Rame MA, Mortemousque I, McGuffog L, Chenevix-Trench G, Pereira-Smith OM, Antoniou AC, Cerón J, Tominaga K, Surrallés J, and Pujana MA

Subjects
Animals, Breast Neoplasms metabolism, Caenorhabditis elegans, Cell Line, DNA Damage, DNA Repair, Fanconi Anemia genetics, Fanconi Anemia Complementation Group D2 Protein genetics, Fanconi Anemia Complementation Group D2 Protein metabolism, Fanconi Anemia Complementation Group N Protein, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Humans, Mice, Mutation, Nuclear Proteins genetics, Nuclear Proteins metabolism, RNA Interference, Rad51 Recombinase genetics, Rad51 Recombinase metabolism, Replication Protein A genetics, Replication Protein A metabolism, Risk Factors, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Two-Hybrid System Techniques, Breast Neoplasms genetics, Transcription Factors genetics, Transcription Factors metabolism
Abstract

Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens., Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk., Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively., Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

Published
2011
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22. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.

Author

Antoniou AC, Beesley J, McGuffog L, Sinilnikova OM, Healey S, Neuhausen SL, Ding YC, Rebbeck TR, Weitzel JN, Lynch HT, Isaacs C, Ganz PA, Tomlinson G, Olopade OI, Couch FJ, Wang X, Lindor NM, Pankratz VS, Radice P, Manoukian S, Peissel B, Zaffaroni D, Barile M, Viel A, Allavena A, Dall'Olio V, Peterlongo P, Szabo CI, Zikan M, Claes K, Poppe B, Foretova L, Mai PL, Greene MH, Rennert G, Lejbkowicz F, Glendon G, Ozcelik H, Andrulis IL, Thomassen M, Gerdes AM, Sunde L, Cruger D, Birk Jensen U, Caligo M, Friedman E, Kaufman B, Laitman Y, Milgrom R, Dubrovsky M, Cohen S, Borg A, Jernström H, Lindblom A, Rantala J, Stenmark-Askmalm M, Melin B, Nathanson K, Domchek S, Jakubowska A, Lubinski J, Huzarski T, Osorio A, Lasa A, Durán M, Tejada MI, Godino J, Benitez J, Hamann U, Kriege M, Hoogerbrugge N, van der Luijt RB, van Asperen CJ, Devilee P, Meijers-Heijboer EJ, Blok MJ, Aalfs CM, Hogervorst F, Rookus M, Cook M, Oliver C, Frost D, Conroy D, Evans DG, Lalloo F, Pichert G, Davidson R, Cole T, Cook J, Paterson J, Hodgson S, Morrison PJ, Porteous ME, Walker L, Kennedy MJ, Dorkins H, Peock S, Godwin AK, Stoppa-Lyonnet D, de Pauw A, Mazoyer S, Bonadona V, Lasset C, Dreyfus H, Leroux D, Hardouin A, Berthet P, Faivre L, Loustalot C, Noguchi T, Sobol H, Rouleau E, Nogues C, Frénay M, Vénat-Bouvet L, Hopper JL, Daly MB, Terry MB, John EM, Buys SS, Yassin Y, Miron A, Goldgar D, Singer CF, Dressler AC, Gschwantler-Kaulich D, Pfeiler G, Hansen TV, Jønson L, Agnarsson BA, Kirchhoff T, Offit K, Devlin V, Dutra-Clarke A, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Schwartz PE, Blank SV, Toland AE, Montagna M, Casella C, Imyanitov E, Tihomirova L, Blanco I, Lazaro C, Ramus SJ, Sucheston L, Karlan BY, Gross J, Schmutzler R, Wappenschmidt B, Engel C, Meindl A, Lochmann M, Arnold N, Heidemann S, Varon-Mateeva R, Niederacher D, Sutter C, Deissler H, Gadzicki D, Preisler-Adams S, Kast K, Schönbuchner I, Caldes T, de la Hoya M, Aittomäki K, Nevanlinna H, Simard J, Spurdle AB, Holland H, Chen X, Platte R, Chenevix-Trench G, and Easton DF

Subjects
Adult, Aged, Aged, 80 and over, Alleles, Apoptosis Regulatory Proteins, Breast Neoplasms pathology, Female, Genotype, Heterozygote, High Mobility Group Proteins, Humans, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Progesterone genetics, Risk Assessment, Risk Factors, Sodium-Bicarbonate Symporters genetics, Survival Analysis, Trans-Activators, Vesicular Transport Proteins genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Mutation
Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Published
2010
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23. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Author

Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM, Guiducci C, Segrè AV, McGee K, McGuffog L, Kartsonaki C, Morrison J, Healey S, Sinilnikova OM, Stoppa-Lyonnet D, Mazoyer S, Gauthier-Villars M, Sobol H, Longy M, Frenay M, GEMO Study Collaborators, Hogervorst FB, Rookus MA, Collée JM, Hoogerbrugge N, van Roozendaal KE, Piedmonte M, Rubinstein W, Nerenstone S, Van Le L, Blank SV, Caldés T, de la Hoya M, Nevanlinna H, Aittomäki K, Lazaro C, Blanco I, Arason A, Johannsson OT, Barkardottir RB, Devilee P, Olopade OI, Neuhausen SL, Wang X, Fredericksen ZS, Peterlongo P, Manoukian S, Barile M, Viel A, Radice P, Phelan CM, Narod S, Rennert G, Lejbkowicz F, Flugelman A, Andrulis IL, Glendon G, Ozcelik H, Toland AE, Montagna M, D'Andrea E, Friedman E, Laitman Y, Borg A, Beattie M, Ramus SJ, Domchek SM, Nathanson KL, Rebbeck T, Spurdle AB, Chen X, Holland H, John EM, Hopper JL, Buys SS, Daly MB, Southey MC, Terry MB, Tung N, Overeem Hansen TV, Nielsen FC, Greene MH, Mai PL, Osorio A, Durán M, Andres R, Benítez J, Weitzel JN, Garber J, Hamann U, Peock S, Cook M, Oliver C, Frost D, Platte R, Evans DG, Lalloo F, Eeles R, Izatt L, Walker L, Eason J, Barwell J, Godwin AK, Schmutzler RK, Wappenschmidt B, Engert S, Arnold N, Gadzicki D, Dean M, Gold B, Klein RJ, Couch FJ, Chenevix-Trench G, Easton DF, Daly MJ, Antoniou AC, Altshuler DM, and Offit K

Subjects
Adult, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 20, DNA-Binding Proteins genetics, Female, Gene Frequency, Genetic Predisposition to Disease genetics, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Middle Aged, Mutation, Penetrance, Receptor, Fibroblast Growth Factor, Type 2 genetics, Risk Factors, Transcription Factors genetics, White People genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide
Abstract

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Published
2010
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24. Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.

Author

Fletcher O, Johnson N, dos Santos Silva I, Orr N, Ashworth A, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Burwinkel B, Bartram CR, Meindl A, Schmutzler RK, Cox A, Brock I, Elliott G, Reed MW, Southey MC, Smith L, Spurdle AB, Hopper JL, Couch FJ, Olson JE, Wang X, Fredericksen Z, Schürmann P, Waltes R, Bremer M, Dörk T, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Hall P, Czene K, Humphreys K, Liu J, Ahmed S, Dunning AM, Maranian M, Pharoah PD, Chenevix-Trench G, Beesley J, Bogdanova NV, Antonenkova NN, Zalutsky IV, Anton-Culver H, Ziogas A, Brauch H, Ko YD, Hamann U, Fasching PA, Strick R, Ekici AB, Beckmann MW, Giles GG, Severi G, Baglietto L, English DR, Milne RL, Benítez J, Arias JI, Pita G, Nordestgaard BG, Bojesen SE, Flyger H, Kang D, Yoo KY, Noh DY, Mannermaa A, Kataja V, Kosma VM, García-Closas M, Chanock S, Lissowska J, Brinton LA, Chang-Claude J, Wang-Gohrke S, Broeks A, Schmidt MK, van Leeuwen FE, Van't Veer LJ, Margolin S, Lindblom A, Humphreys MK, Morrison J, Platte R, Easton DF, and Peto J

Subjects
Ataxia Telangiectasia Mutated Proteins, Case-Control Studies, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Genotype, Humans, Polymorphism, Single Nucleotide, Risk Factors, Breast Neoplasms genetics, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Mutation, Missense, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins genetics
Abstract

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious., Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium., Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02)., Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer., Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility., ((c) 2010 AACR.)

Published
2010
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25. Fine scale mapping of the breast cancer 16q12 locus.

Author

Udler MS, Ahmed S, Healey CS, Meyer K, Struewing J, Maranian M, Kwon EM, Zhang J, Tyrer J, Karlins E, Platte R, Kalmyrzaev B, Dicks E, Field H, Maia AT, Prathalingam R, Teschendorff A, McArthur S, Doody DR, Luben R, Caldas C, Bernstein L, Kolonel LK, Henderson BE, Wu AH, Le Marchand L, Ursin G, Press MF, Lindblom A, Margolin S, Shen CY, Yang SL, Hsiung CN, Kang D, Yoo KY, Noh DY, Ahn SH, Malone KE, Haiman CA, Pharoah PD, Ponder BA, Ostrander EA, Easton DF, and Dunning AM

Subjects
Chromosome Mapping, Female, Genetic Markers, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Chromosomes, Human, Pair 16 genetics, Genetic Predisposition to Disease
Abstract

Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5' end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case-control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case-control studies exhibit a different pattern of association suggestive of an additional causative variant.

Published
2010
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26. CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen.

Author

Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Shah M, Ingle S, Greenberg D, Earl HM, Dunning AM, Pharoah PD, and Caldas C

Subjects
Adult, Aged, Antineoplastic Agents, Hormonal metabolism, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms pathology, Chemotherapy, Adjuvant statistics & numerical data, Cohort Studies, Cytochrome P-450 CYP2D6 metabolism, Female, Gene Frequency, Genotype, Humans, Middle Aged, Proportional Hazards Models, Survival Analysis, Tamoxifen metabolism, Treatment Outcome, United Kingdom, Young Adult, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Cytochrome P-450 CYP2D6 genetics, Polymorphism, Single Nucleotide, Tamoxifen therapeutic use
Abstract

Introduction: Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen., Methods: This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis., Results: In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups., Conclusions: CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.

Published
2010
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27. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Author

Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H, Heikkinen T, Simard J, Spurdle AB, Beesley J, Chen X, Neuhausen SL, Ding YC, Couch FJ, Wang X, Fredericksen Z, Peterlongo P, Peissel B, Bonanni B, Viel A, Bernard L, Radice P, Szabo CI, Foretova L, Zikan M, Claes K, Greene MH, Mai PL, Rennert G, Lejbkowicz F, Andrulis IL, Ozcelik H, Glendon G, Gerdes AM, Thomassen M, Sunde L, Caligo MA, Laitman Y, Kontorovich T, Cohen S, Kaufman B, Dagan E, Baruch RG, Friedman E, Harbst K, Barbany-Bustinza G, Rantala J, Ehrencrona H, Karlsson P, Domchek SM, Nathanson KL, Osorio A, Blanco I, Lasa A, Benítez J, Hamann U, Hogervorst FB, Rookus MA, Collee JM, Devilee P, Ligtenberg MJ, van der Luijt RB, Aalfs CM, Waisfisz Q, Wijnen J, van Roozendaal CE, Peock S, Cook M, Frost D, Oliver C, Platte R, Evans DG, Lalloo F, Eeles R, Izatt L, Davidson R, Chu C, Eccles D, Cole T, Hodgson S, Godwin AK, Stoppa-Lyonnet D, Buecher B, Léoné M, Bressac-de Paillerets B, Remenieras A, Caron O, Lenoir GM, Sevenet N, Longy M, Ferrer SF, Prieur F, Goldgar D, Miron A, John EM, Buys SS, Daly MB, Hopper JL, Terry MB, Yassin Y, Singer C, Gschwantler-Kaulich D, Staudigl C, Hansen Tv, Barkardottir RB, Kirchhoff T, Pal P, Kosarin K, Offit K, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Schwartz PE, Blank SV, Toland AE, Montagna M, Casella C, Imyanitov EN, Allavena A, Schmutzler RK, Versmold B, Engel C, Meindl A, Ditsch N, Arnold N, Niederacher D, Deissler H, Fiebig B, Suttner C, Schönbuchner I, Gadzicki D, Caldes T, de la Hoya M, Pooley KA, Easton DF, and Chenevix-Trench G

Subjects
Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 2 genetics, Chromosomes, Human, Pair 8 genetics, Genetic Variation, Heterozygote, Microfilament Proteins genetics
Abstract

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Published
2009
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28. No evidence that GATA3 rs570613 SNP modifies breast cancer risk.

Author

Johnatty SE, Couch FJ, Fredericksen Z, Tarrell R, Spurdle AB, Beesley J, Chen X, Gschwantler-Kaulich D, Singer CF, Fuerhauser C, Fink-Retter A, Domchek SM, Nathanson KL, Pankratz VS, Lindor NM, Godwin AK, Caligo MA, Hopper J, Southey MC, Giles GG, Justenhoven C, Brauch H, Hamann U, Ko YD, Heikkinen T, Aaltonen K, Aittomäki K, Blomqvist C, Nevanlinna H, Hall P, Czene K, Liu J, Peock S, Cook M, Platte R, Gareth Evans D, Lalloo F, Eeles R, Pichert G, Eccles D, Davidson R, Cole T, Cook J, Douglas F, Chu C, Hodgson S, Paterson J, Hogervorst FB, Rookus MA, Seynaeve C, Wijnen J, Vreeswijk M, Ligtenberg M, van der Luijt RB, van Os TA, Gille HJ, Blok MJ, Issacs C, Humphreys MK, McGuffog L, Healey S, Sinilnikova O, Antoniou AC, Easton DF, and Chenevix-Trench G

Subjects
Female, Genes, BRCA1, Genes, BRCA2, Genotype, Humans, Linkage Disequilibrium, Mutation, Risk Factors, Breast Neoplasms genetics, GATA3 Transcription Factor genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract

GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P (trend) = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (OR(per-allele) = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (OR(per-allele) = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RR(per-allele) = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RR(per-allele) = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.

Published
2009
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29. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042.

Author

Milne RL, Benítez J, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Arias JI, Zamora MP, Burwinkel B, Bartram CR, Meindl A, Schmutzler RK, Cox A, Brock I, Elliott G, Reed MW, Southey MC, Smith L, Spurdle AB, Hopper JL, Couch FJ, Olson JE, Wang X, Fredericksen Z, Schürmann P, Bremer M, Hillemanns P, Dörk T, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Hall P, Czene K, Liu J, Li Y, Ahmed S, Dunning AM, Maranian M, Pharoah PD, Chenevix-Trench G, Beesley J, Bogdanova NV, Antonenkova NN, Zalutsky IV, Anton-Culver H, Ziogas A, Brauch H, Justenhoven C, Ko YD, Haas S, Fasching PA, Strick R, Ekici AB, Beckmann MW, Giles GG, Severi G, Baglietto L, English DR, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Turnbull C, Hines S, Renwick A, Rahman N, Nordestgaard BG, Bojesen SE, Flyger H, Kang D, Yoo KY, Noh DY, Mannermaa A, Kataja V, Kosma VM, García-Closas M, Chanock S, Lissowska J, Brinton LA, Chang-Claude J, Wang-Gohrke S, Shen CY, Wang HC, Yu JC, Chen ST, Bermisheva M, Nikolaeva T, Khusnutdinova E, Humphreys MK, Morrison J, Platte R, and Easton DF

Subjects
Adult, Aged, Asian People genetics, Breast Neoplasms pathology, Carcinoma, Ductal, Breast chemistry, Carcinoma, Ductal, Breast genetics, Carcinoma, Intraductal, Noninfiltrating chemistry, Carcinoma, Intraductal, Noninfiltrating genetics, Case-Control Studies, Confidence Intervals, Confounding Factors, Epidemiologic, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Odds Ratio, Receptors, Progesterone genetics, Biomarkers, Tumor analysis, Breast Neoplasms chemistry, Breast Neoplasms genetics, Neoplasms, Hormone-Dependent chemistry, Neoplasms, Hormone-Dependent genetics, Polymorphism, Single Nucleotide, Receptors, Estrogen analysis, White People genetics
Abstract

Background: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium., Methods: 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided., Results: We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P(trend) = 1.0 x 10(-19)). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P > or = .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10(-15)) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10(-14)) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002)., Conclusion: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

Published
2009
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30. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

Author

Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Stratton MR, Rahman N, Jacobs K, Prentice R, Anderson GL, Rajkovic A, Curb JD, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver WR, Bojesen S, Nordestgaard BG, Flyger H, Dörk T, Schürmann P, Hillemanns P, Karstens JH, Bogdanova NV, Antonenkova NN, Zalutsky IV, Bermisheva M, Fedorova S, Khusnutdinova E, Kang D, Yoo KY, Noh DY, Ahn SH, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Garcia-Closas M, Lissowska J, Brinton L, Peplonska B, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Hopper JL, Southey MC, Smith L, Spurdle AB, Schmidt MK, Broeks A, van Hien RR, Cornelissen S, Milne RL, Ribas G, González-Neira A, Benitez J, Schmutzler RK, Burwinkel B, Bartram CR, Meindl A, Brauch H, Justenhoven C, Hamann U, Chang-Claude J, Hein R, Wang-Gohrke S, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kataja V, Olson JE, Wang X, Fredericksen Z, Giles GG, Severi G, Baglietto L, English DR, Hankinson SE, Cox DG, Kraft P, Vatten LJ, Hveem K, Kumle M, Sigurdson A, Doody M, Bhatti P, Alexander BH, Hooning MJ, van den Ouweland AM, Oldenburg RA, Schutte M, Hall P, Czene K, Liu J, Li Y, Cox A, Elliott G, Brock I, Reed MW, Shen CY, Yu JC, Hsu GC, Chen ST, Anton-Culver H, Ziogas A, Andrulis IL, Knight JA, Beesley J, Goode EL, Couch F, Chenevix-Trench G, Hoover RN, Ponder BA, Hunter DJ, Pharoah PD, Dunning AM, Chanock SJ, and Easton DF

Subjects
Breast Neoplasms pathology, Chromosome Mapping, Disease Susceptibility metabolism, Female, Genome, Human, Genotype, Humans, Breast Neoplasms genetics, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 3 genetics, Genetic Predisposition to Disease genetics
Abstract

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

Published
2009
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31. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kämpjärvi K, Nevanlinna H, Simard J, Beesley J, Chen X, Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopade OI, Blum JL, Couch FJ, Peterlongo P, Manoukian S, Barile M, Radice P, Szabo CI, Pereira LH, Greene MH, Rennert G, Lejbkowicz F, Barnett-Griness O, Andrulis IL, Ozcelik H, Gerdes AM, Caligo MA, Laitman Y, Kaufman B, Milgrom R, Friedman E, Domchek SM, Nathanson KL, Osorio A, Llort G, Milne RL, Benítez J, Hamann U, Hogervorst FB, Manders P, Ligtenberg MJ, van den Ouweland AM, Peock S, Cook M, Platte R, Evans DG, Eeles R, Pichert G, Chu C, Eccles D, Davidson R, Douglas F, Godwin AK, Barjhoux L, Mazoyer S, Sobol H, Bourdon V, Eisinger F, Chompret A, Capoulade C, Bressac-de Paillerets B, Lenoir GM, Gauthier-Villars M, Houdayer C, Stoppa-Lyonnet D, Chenevix-Trench G, and Easton DF

Subjects
Adult, Aged, Female, Germ-Line Mutation, Humans, Middle Aged, Polymorphism, Single Nucleotide, Risk, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease genetics, MAP Kinase Kinase Kinase 1 genetics, Receptor, Fibroblast Growth Factor, Type 2 genetics
Abstract

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Published
2008
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32. Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Spurdle, Amanda B, Couch, Fergus J, Parsons, Michael T, McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K, Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L, Domchek, Susan M, Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Åke, Andrulis, Irene L, Miron, Alexander, Hansen, Thomas VO, Caldes, Trinidad, Neuhausen, Susan L, Toland, Amanda E, Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K, Osorio, Ana, Factor, Rachel E, Terry, Mary B, Rebbeck, Timothy R, Karlan, Beth Y, Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul DP, Blows, Fiona M, Dunning, Alison M, Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Slamon, Dennis J, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A, Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J, and Brinton, Louise

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Prevention, Genetics, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Adult, Age Factors, Aged, Breast Neoplasms, Carcinoma, Female, Genes, BRCA1, Genes, BRCA2, Humans, Likelihood Functions, Middle Aged, Mutation, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Triple Negative Breast Neoplasms, ABCTB Investigators, EMBRACE Group, GENICA Network, HEBON Group, kConFab Investigators, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Published
2014

33. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna Marie, Neuhausen, Susan L, Fox, Stephen, Karlan, Beth Y, Mitchell, Gillian, James, Paul, Thull, Darcy L, Zorn, Kristin K, Carter, Natalie J, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Ramus, Susan J, Nussbaum, Robert L, Olopade, Olufunmilayo I, Rantala, Johanna, Yoon, Sook-Yee, Caligo, Maria A, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge Sokilde, Thomassen, Mads, Jensen, Uffe Birk, Toland, Amanda Ewart, Senter, Leigha, Andrulis, Irene L, Glendon, Gord, Hulick, Peter J, Imyanitov, Evgeny N, Greene, Mark H, Mai, Phuong L, Singer, Christian F, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus J, Hallberg, Emily, Ruddy, Kathryn J, Sharma, Priyanka, Kim, Sung-Won, kConFab Investigators, Teixeira, Manuel R, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Arason, Adalgeir, Johannsson, Oskar Th, Barkardottir, Rosa B, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel Angel, Balmaña, Judith, Diez, Orland, Ivady, Gabriella, Papp, Janos, Olah, Edith, Kwong, Ava, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Nevanlinna, Heli, Aittomäki, Kristiina, Perez Segura, Pedro, Caldes, Trinidad, Van Maerken, Tom, Poppe, Bruce, Claes, Kathleen BM, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Varon-Mateeva, Raymonda, Wand, Dorothea, Godwin, Andrew K, Evans, D Gareth, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, and Platte, Radka

Subjects
Male, Adult, endocrine system diseases, Oncology and Carcinogenesis, Breast Neoplasms, Genotype-phenotype correlations, EMBRACE, Histologic grade, BRCA1/2, Breast Cancer, polycyclic compounds, Pathology, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Polymorphism, skin and connective tissue diseases, Neoplasm Staging, Aged, Cancer, BRCA2 Protein, BRCA1 Protein, Single Nucleotide, Middle Aged, Male breast cancer, Mutation, kConFab Investigators, Female, Hereditary Breast and Ovarian Cancer Research Group Netherlands
Abstract

BackgroundBRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).MethodsWe characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.ResultsAmong BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)).ConclusionsOn the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Published
2016

34. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Author

Peterlongo, Paolo, Chang-Claude, J., Moysich, Kirsten, Rudolph, Anja, Schmutzler, Rita, Simard, Jacques, Soucy, Penny, Tea, Rosalind, Easton, Douglas, Hamann, Ute, Wilkening, Stefan, Chen, Bowang, Rookus, Matti, Schmidt, Marjanka, van der Baan, Frederieke, Spurdle, Amanda, Walker, Logan, Lose, Felicity, Mai, Ana, Montagna, Marc, Matricardi, Laura, Lubinski, Jan, Jakubowska, Anna, Gómez Garcia, Encarna, Olopade, Olufunmilayo, Nussbaum, Robert, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Arun, Anders, Karlan, Beth, Orsulic, Sandra, Lester, Jenny, Chung, Wendy, Miron, Alex, Southey, Melissa, Goldgar, David, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia, Van Rensburg, Elizabeth, Ding, Yuan Chun, Neuhausen, Susan, Hansen, Hans, Gerdes, Anne-Marie, Ejlertsen, Bent, Jønson, Lars, Osorio, Ana, Martínez-Bouzas, Cristina, Benitez, Javier, Conway, Edye, Blazer, Kathleen, Weitzel, Jeffrey, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniel, Scuvera, Giulietta, Barile, Monica, Ficarazzi, Filomena, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Giannini, Giuseppe, Papi, Laura, Martayan, Aline, Tibiletti, Maria Grazia, Radice, Paolo, Vratimos, Athanassios, Fostira, Florentia, Garber, Judy, Donaldson, Michael, Brewer, Carole, Foo, Claire, Evans, D Gareth R, Frost, Debra, Eccles, Diana, Kennedy, Angela, Cook, Jackie, Tischkowitz, Marc, Lee, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy, Kennedy, M John, Rogers, Mark, Porteous, Mary, Morrison, Patrick, Platte, Radka, Davidson, Rosemarie, Hodgson, Georg, Ellis, Steve, Cole, Trevor, Godwin, Andrew, Claes, Kathleen, Van Maerken, Tom, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hans, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Wang, Shan, Bressac-de Paillerets, Brigitte, Buecher, Bruno, Delnatte, Capucine, Houdayer, Claude, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Coupier, Isabelle, Barjhoux, Laure, Venat-Bouvet, Lauren, Golmard, Lisa, Boutry-Kryza, Nadia, Sinilnikova, Olga, Caron, Olivier, Pujol, Pascal, Mazoyer, Sylvie, Belotti, Muriel, Piedmonte, Marion, Friedlander, Michael, Rodriguez, Gustavo, Copeland, Larry, De La Hoya, Miguel, Segura, Pedro Perez, Nevanlinna, Heli, Aittomäki, Kristiina, Van Os, Theo, Meijers-Heijboer, Hanne, van der Hout, Annemarie, Vreeswijk, Maaike, Hoogerbrugge, Nicoline, Ausems, Margreet, van Doorn, Helena, Collée, J Margriet, Olah, Edith, Diez, Orland, Blanco, Ignacio, Lazaro, Conxi, Brunet, Joan, Feliubadaló, Lídia, Cybulski, Cezary, Gronwald, Jacek, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Sukiennicki, Grzegorz, Arason, Adalgeir, Chiquette, Jocelyne, Teixeira, Manuel, Olswold, Curtis, Couch, Fergus, Lindor, Noralane, Wang, Xianshu, Szabo, Csilla, Offit, Kenneth, Corines, Marina, Jacobs, Lauren, Robson, Mark, Zhang, Liying, Joseph, Vijai, Berger, Andreas, Singer, Christian, Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Phelan, Catherine, Greene, Mark, Mai, Phuong, Rennert, Gad, Mulligan, Anna, Glendon, Gord, Tchatchou, Sandrine, Andrulis, Irene, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Søkilde, Thomassen, Mads, Jensen, Uffe Birk, Laitman, Yael, Rantala, Johanna, von Wachenfeldt, Anna, Ehrencrona, Hans, Askmalm, Marie Stenmark, Borg, Åke, Kuchenbaecker, Karoline, Mcguffog, Lesley, Barrowdale, Daniel, Healey, Sue, Lee, Andrew, Pharoah, Paul, Chenevix-Trench, Georgia, Antoniou, Antonis, Friedman, Eitan, Schmutzler, K., Eeles, A., Rookus, A., Schmidt, K., Maia, A., Gomez Garcia, B., Rebbeck, R., Arun, K., Chung, K., Dorfling, M., van Rensburg, J., Ding, C., Hansen, O., Jonson, L., Martinez-Bouzas, C., Donaldson, A., Evans, R., Brady, A., Adlard, J., Kennedy, J., Hodgson, S., Godwin, K., Wang-Gohrke, S., Sinilnikova, M., Rodriguez, C., Copeland, J., Aittomaki, K., van Os, A., Meijers-Heijboer, J., Vreeswijk, P., Van Doorn, C., Collee, J., Teixeira, R., Couch, J., Lindor, M., Singer, F., Tea, K., Phelan, M., Andrulis, L., Pedersen, S., Askmalm, S., Borg, A., Chen, G., Human genetics, CCA - Oncogenesis, RS: GROW - Oncology, Department of Organisation and Personnel Management, Obstetrics & Gynecology, Clinical Genetics, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Human Genetics, Cancer Center Amsterdam, and Amsterdam Reproduction & Development (AR&D)

Subjects
Oncology, Candidate gene, endocrine system diseases, Epidemiology, Genes, BRCA2, Genes, BRCA1, Cohort Studies, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Young adult, skin and connective tissue diseases, Genetics, Ovarian Neoplasms, 0303 health sciences, Single Nucleotide, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Association, 03 medical and health sciences, Ovarian Neoplasms/genetics, Young Adult, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Polymorphism, Genotyping, Gene, 030304 developmental biology, Genetic association, Retrospective Studies, Mutation, business.industry, Retrospective cohort study, Genes, BRCA1/physiology, BRCA1, medicine.disease, BRCA2, Genes, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Ovarian cancer, Genes, BRCA2/physiology
Abstract

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR. European Community (COGS) [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/ A15007, C5047/A10692, C1287/A16563, C1287/A17523, C5047/A8385]; NIH [CA128978, R01-CA102776, R01CA083855]; Post-Cancer GWAS initiative [1U19CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute [UM1 CA164920, RC4CA153828]; Research Council of Lithuania [LIG-07/2012]; Cancer Association of South Africa (CANSA); Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI12/00070]; Mutua Madrilena Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry (COH-CCGCRN); Fondazione IRCCS Istituto Nazionale dei Tumori; DKFZ; NIHR grant to the Biomedical Research Centre, Manchester; NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; German Cancer Aid [109078]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Helsinki University Central Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society and the Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005]; BBMRI [NWO 184.021.007/CP46]; Hungarian Research Grants [KTIA OTKA CK-80745, OTKA K-112228]; Asociacion Espanola Contra el Cancer; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, 2009SGR290]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Ministero della Salute; Istituto Oncologico Veneto; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; David and Margaret T. Grohne Family Foundation; Ting Tsung and Wei Fong Chao Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Ohio State University Comprehensive Cancer Center; Swedish Cancer Society; Women's Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute - American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; NEYE Foundation; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology:; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; NCI's Community Clinical Oncology Program (CCOP) grant [CA 101165]; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Israel Cancer Association; Israeli Inherited Breast Cancer Consortium; Susan G. Komen Foundation; Basser Research Center; ISCIII [RD12/00369/0006]; European Regional Development funds, Spain; Morris and Horowitz Families Endowed Professorship; Chancellors Distinguished Chair in Biomedical Sciences Professorship; Intramural Research Program of the US National Cancer Institute; NIH; Westat, Inc; [PBZ_KBN_122/P05/2004]; [1R01 CA149429-01]; [5U01CA113916]; [R01CA140323]; [NO2-CP-11019- 50]; [N02-CP-65504]; Associazione Italiana per la Ricerca sul Cancro; Cancer Research UK [11174, 10119, 17528, 17523, 15007, 10124, 10118, 16561, 16563]; National Institute for Health Research [NF-SI-0510-10096] info:eu-repo/semantics/publishedVersion

Published
2015

35. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Spurdle, Amanda B, Couch, Fergus J, Parsons, Michael T, McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K, Wang, Qin, Healey, Sue, Schmutzler, Rita, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L, Domchek, Susan M, Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Åke, Andrulis, Irene L, Miron, Alexander, Hansen, Thomas VO, Caldes, Trinidad, Neuhausen, Susan L, Toland, Amanda E, Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K, Osorio, Ana, Factor, Rachel E, Terry, Mary B, Rebbeck, Timothy R, Karlan, Beth Y, Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul DP, Blows, Fiona M, Dunning, Alison M, Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Slamon, Dennis J, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A, Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J, and Brinton, Louise

Subjects
Adult, endocrine system diseases, Oncology and Carcinogenesis, ABCTB Investigators, Breast Neoplasms, Triple Negative Breast Neoplasms, HEBON Group, EMBRACE Group, ErbB-2, Receptors, Breast Cancer, Genetics, Humans, Oncology & Carcinogenesis, skin and connective tissue diseases, Progesterone, Neoplasm Staging, Aged, Cancer, screening and diagnosis, Likelihood Functions, Prevention, Carcinoma, Age Factors, Middle Aged, BRCA1, Estrogen, BRCA2, Detection, Genes, Mutation, kConFab Investigators, Female, GENICA Network, Neoplasm Grading, Receptor, 4.2 Evaluation of markers and technologies
Abstract

IntroductionThe distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.MethodsSelection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ResultsER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).ConclusionsThese results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Published
2014

36. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author

Kuchenbaecker, Karoline B, Neuhausen, Susan L, Robson, Mark, Barrowdale, Daniel, McGuffog, Lesley, Mulligan, Anna Marie, Andrulis, Irene L, Spurdle, Amanda B, Schmidt, Marjanka K, Schmutzler, Rita K, Engel, Christoph, Wappenschmidt, Barbara, Nevanlinna, Heli, Thomassen, Mads, Southey, Melissa, Radice, Paolo, Ramus, Susan J, Domchek, Susan M, Nathanson, Katherine L, Lee, Andrew, Healey, Sue, Nussbaum, Robert L, Rebbeck, Timothy R, Arun, Banu K, James, Paul, Karlan, Beth Y, Lester, Jenny, Cass, Ilana, Breast Cancer Family Registry, Terry, Mary Beth, Daly, Mary B, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, v O Hansen, Thomas, Ejlertsen, Bent, Gerdes, Anne-Marie, Nielsen, Finn C, Dennis, Joe, Cunningham, Julie, Hart, Steven, Slager, Susan, Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N, Tafur, Isaac, Hander, Mary, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Roversi, Gaia, Scuvera, Giulietta, Bonanni, Bernardo, Mariani, Paolo, Volorio, Sara, Dolcetti, Riccardo, Varesco, Liliana, Papi, Laura, Tibiletti, Maria Grazia, Giannini, Giuseppe, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE Study, Douglas, Fiona, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Ong, Kai-ren, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Ellis, Steve, Godwin, Andrew K, Rhiem, Kerstin, Meindl, Alfons, and Ditsch, Nina

Subjects
Adult, Heterozygote, Oncology and Carcinogenesis, Breast Neoplasms, Lobular, GEMO Study Collaborators, ErbB-2, Breast Cancer Family Registry, Clinical Research, Ductal, Receptors, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Breast, Oncology & Carcinogenesis, Aetiology, skin and connective tissue diseases, HEBON, Progesterone, Alleles, Neoplasm Staging, Aged, Cancer, Prevention, Carcinoma, Middle Aged, BRCA1, Estrogen, BRCA2, EMBRACE Study, Genes, Female, KConFab Investigators, Neoplasm Grading, CIMBA, Receptor
Abstract

IntroductionMore than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.MethodsWe used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.ResultsThe estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P

Published
2014

37. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Osorio, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco Guillermo, Ignacio, De la Hoya, Miguel, Durán, Mercedes, Diez, Orland, Ramon y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, None, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I., Beattie, Mary S., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John L, Terry, Mary Beth, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas v. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana M, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jörg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Claes, Kathleen, Piedmonte, Marion, Tucker, Kathy, Backes, Floor, Rodríguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Rookus, Matti A., van Os, Theo A. M., van der Kolk, Lizet, de Lange, J. L., Meijers-Heijboer, Hanne E. J., van der Hout, A. H., van Asperen, Christi J., Gómez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collée, J. Margriet, van Deurzen, Carolien H. M., van der Luijt, Rob B., Devilee, Peter, HEBON, None, Olah, Edith, Lázaro, Conxi, Teulé, Alex, Menéndez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Johannsson, Oskar Th., Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Investigators, kConFab, Olswold, Curtis, Guidugli, Lucia, Lindor, Noralane, Slager, Susan, Szabo, Csilla I., Vijai, Joseph, Robson, Mark, Kauff, Noah, Zhang, Liying, Rau-Murthy, Rohini, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Geschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Berger, Andreas, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Lejbkowicz, Flavio, Andrulis, Irene L., Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, Universitat Autònoma de Barcelona, Pediatric Surgery, Clinical Genetics, Pathology, Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 2Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 5Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain. 6IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. 7Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 9Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain. 10Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain. 11Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 12Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece. 13Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain. 14Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain. 15Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 16Department of Oncology, Lund University, Lund, Sweden. 17Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. 18Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 19Department of Oncology, Lund University Hospital, Lund, Sweden. 20Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 21Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America. 22Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America. 23Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. 24Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. 25University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 26Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. 27Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America. 28Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America. 29Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America. 30Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia. 31Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia. 32Department of Epidemiology, Columbia University, New York, New York, United States of America. 33Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. 34Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania. 35Department of Genetics, University of Pretoria, Pretoria, South Africa. 36Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America. 37Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 39Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 40Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America. 41Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 42Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 43IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 44Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 45Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 46Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 47Department of Molecular Medicine, 'Sapienza' University, Rome, Italy. 48UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy. 49Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 50Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 51Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 52South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom. 53Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom. 54Yorkshire Regional Genetics Service, Leeds, United Kingdom. 55Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom. 56West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom. 57Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 58Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom. 59Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom. 60Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 61Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom. 62Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 63South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom. 64North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 65Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom. 66Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom. 67South West Regional Genetics Service, Bristol, United Kingdom. 68Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire. 69Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom. 70Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America. 71Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. 72Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 73Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 74Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 75Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 76Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 77Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 78Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 79Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 80Institute of Human Genetics, University of Münster, Münster, Germany. 81Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 82Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany. 83Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany. 84Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 85Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 86INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 87Center for Medical Genetics, Ghent University, Ghent, Belgium. 88Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America. 89Prince of Wales Hospital. Sydney, Australia. 90Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America. 91Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America. 92Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America. 93For Tufts Medical Center, Boston, Massachusetts, United States of America. 94Yale University School of Medicine, New Haven, Connecticut, United States of America. 95Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 96Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 97Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 98Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands. 99Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 100University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 101Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands. 102Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands. 103Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 104Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 105Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 106Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 107Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 108The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands. 109Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 110Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 111Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 112Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland. 113Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland. 114Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France. 115Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 116Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 117Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia. 118Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia. 119Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. 120Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 121Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America. 122Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America. 123Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 124Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 125Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 126Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 127Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. 128Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America. 129Clalit National Israeli Cancer Control Center, Haifa, Israel. 130Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 131Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 132Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 133Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America. 134Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 135Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 136Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 137Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 138Sheba Medical Center, Tel Aviv, Israel. 139Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 140Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 141Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain, Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain., SWE-BRCA, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Unión Europea, Cancer Research UK (Reino Unido), United States of Department of Health & Human Services, Canadian Institutes of Health Research, Susan G. Komen Breast Cancer Foundation, Ralph and Marion Falk Medical Research Trust, Research Council (Lituania), University of Kansas. Cancer Center (Estados Unidos), National Institute for Health Research (Reino Unido), Deutsche Krebshilfe, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Hungarian Scientific Research Fund (Hungría), Canadian Breast Cancer Network, Ministère du Développement économique, de Innovation et de Exportation (Canadá), Westat (Estados Unidos), Department of Obstetrics and Gynecology, Clinicum, Universitat de Barcelona, Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, CCA - Oncogenesis, Fundación Mutua Madrileña Automovilista, Fundacion Asociacion Espanola Contra el Cancer (AECC), Instituto de Salud Carlos III - ISCIII, European Union (EU), Cancer Research UK, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Canadian Institutes of Health Research (CIHR), Research Council of Lithuania, University of Kansas Cancer Center, National Institute for Health Research (NIHR), Academy of Finland, KWF Kankerbestrijding, Netherlands Organization for Scientific Research (NWO), Pink Ribbon grant, Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA), Canadian Breast Cancer Research Alliance-grant, Ministry of Economic Development, Innovation and Export Trade, and Westat, Inc, Rockville, MD

Subjects
Cancer Research, 24 Ciencias de la Vida, DNA Repair, endocrine system diseases, ADN, Càncer d'ovari, Synthetic lethality, BRCA1 Protein/genetics, DNA Glycosylases, 0302 clinical medicine, DNA Glycosylases/genetics, Brjóstakrabbamein, Genotype, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Glicosilasas, INVESTIGATORS, skin and connective tissue diseases, OGG1, Genetics (clinical), Genetics, DAMAGE, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, SINGLE-NUCLEOTIDE POLYMORPHISMS, COMMON VARIANTS, Base excision repair, Middle Aged, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, NEIL2, Female, Medical Genetics, Research Article, BRCA1, BRCA2, Adult, Risk, Ovarian Neoplasms/genetics, lcsh:QH426-470, Adolescent, DNA repair, education, Single-nucleotide polymorphism, Breast Neoplasms, DNA Repair/genetics, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Polymorphism, Single Nucleotide/genetics, SDG 3 - Good Health and Well-being, Ovarian cancer, Cancer Genetics, BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, BRCA2 Protein/genetics, CONSORTIUM, Biology and Life Sciences, Arfgengi, lcsh:Genetics, DNA glycosylase, Cancer research, 3111 Biomedicine, GENETIC MODIFIERS, Genètica
Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p, Author Summary Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.

Published
2014

38. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author

Gaudet, Mia M., Kuchenbaecker, Karoline B., Vijai, Joseph, Klein, Robert J., Kirchhoff, Tomas, McGuffog, Lesley, Barrowdale, Daniel, Dunning, Alison M., Lee, Andrew, Dennis, Joe, Healey, Sue, Dicks, Ed, Soucy, Penny, Sinilnikova, Olga M., Pankratz, Vernon S., Wang, Xianshu, Eldridge, Ronald C., Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Hogervorst, Frans B.L., Peock, Susan, Stoppa-Lyonnet, Dominique, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Peterlongo, Paolo, Schmutzler, Rita K., Nathanson, Katherine L., Piedmonte, Marion, Singer, Christian F., Thomassen, Mads, Sokolowska, Johanna, Bronner, Myriam, Hansen, Thomas V.O., Neuhausen, Susan L., Blanco, Ignacio, Greene, Mark H., Garber, Judith, Weitzel, Jeffrey N., Andrulis, Irene L., Goldgar, David E., D'Andrea, Emma, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, van Rensburg, Elizabeth J., Arason, Adalgeir, Rennert, Gad, van den Ouweland, Ans M.W., van der Hout, Annemarie H., Kets, Carolien M., Aalfs, Cora M., Wijnen, Juul T., Ausems, Margreet G.E.M., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Jacobs, Chris, Adlard, Julian, Tischkowitz, Marc, Porteous, Mary, Damiola, Francesca, Golmard, Lisa, Barjhoux, Laure, Longy, Michel, Belotti, Muriel, Ferrer, Sandra Fert, Mazoyer, Sylvie, Spurdle, Amanda B., Manoukian, Siranoush, Barile, Monica, Genuardi, Maurizio, Arnold, Norbert, Meindl, Alfons, Sutter, Christian, Wappenschmidt, Barbara, Domchek, Susan M., Pfeiler, Georg, Friedman, Eitan, Jensen, Uffe Birk, Robson, Mark, Shah, Sohela, Lazaro, Conxi, Mai, Phuong L., Benitez, Javier, Southey, Melissa C., Schmidt, M. K., Fasching, Peter A., Peto, Julian, Humphreys, Manjeet K., Wang, Qin, Michailidou, Kyriaki, Sawyer, Elinor J., Burwinkel, Barbara, Guénel, Pascal, Bojesen, Stig E., Milne, Roger L., Brenner, Hermann, Lochmann, Magdalena, Brauch, Hiltrud, Ko, Yon Dschun, Baisch, Christian, Fischer, Hand Peter, Bruening, Thomas, Pesch, Beate, Rabstein, Sylvia, Spickenheuer, Anne, Aittomäki, Kristiina, Dörk, Thilo, Margolin, Sara, Mannermaa, Arto, Lambrechts, Diether, Chang-Claude, Jenny, Radice, Paolo, Giles, Graham G., Haiman, Christopher A., Winqvist, Robert, Devillee, Peter, García-Closas, Montserrat, Schoof, Nils, Hooning, M. J., Cox, Angela, Pharoah, Paul D.P., Jakubowska, Anna, Orr, Nick, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Hall, Per, Couch, Fergus J., Simard, Jacques, Altshuler, David, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Offit, Kenneth, Rookus, M. A., van Leeuwen, F. E., Verhoef, S., de Lange, J. L., Collée, J. M., Seynaeve, C., van Deurzen, C. H.M., van Asperen, C. J., Tollenaar, R. A., Devilee, P., van Cronenburg, T. C.T.E.F., Mensenkamp, A. R., van der Luijt, R. B., van Os, T. A.M., Gille, J. J.P., Waisfisz, Q., Meijers-Heijboer, H. E.J., Gómez-Garcia, E. B., Blok, M. J., Oosterwijk, J. C., Mourits, M. J., de Bock, G. H., Vasen, H. F., Miedzybrodzka, Zosia, Gregory, Helen, Morrison, Patrick, Jeffers, Lisa, Cole, Trevor, Ong, Kai ren, Hoffman, Jonathan, Donaldson, Alan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Rogers, Mark T., McCann, Emma, Kennedy, M. John, Barton, David, Drummond, Sarah, Brewer, Carole, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Davidson, Rosemarie, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Izatt, Louise, Langman, Caroline, Brady, Angela, Dorkins, Huw, Melville, Athalie, Randhawa, Kashmir, Barwell, Julian, Serra-Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Side, Lucy, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Douglas, Fiona, Claber, Oonagh, Collier, Rebecca, Jobson, Irene, Walker, Lisa, McLeod, Diane, Durell, Sarah, Stayner, Barbara, Eeles, Rosalind A., Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern-Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Cook, Jackie, Quarrell, Oliver, Bardsley, Cathryn, Hodgson, Shirley, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Eccles, Diana, Lucassen, Anneke, Crawford, Gillian, McBride, Donna, Smalley, Sarah, Sinilnikova, Olga, Verny-Pierre, Carole, Giraud, Sophie, Léone, Mélanie, Gauthier-Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Tirapo, Carole, de Pauw, Antoine, Bressac-de-Paillerets, Brigitte, Caron, Olivier, Bignon, Yves Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Handallou, Sandrine, Hardouin, Agnés, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Rouleau, Etienne, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Dreyfus, Hélène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Frénay, Marc, Vénat-Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Lynch, Henry T., Snyder, Carrie L., Clinical Genetics, Medical Oncology, Human Genetics, Human genetics, EMGO - Quality of care, Anesthesiology, CCA - Oncogenesis, CCA - Cancer biology and immunology, Epidemiology and Data Science, Department of Obstetrics and Gynecology, Clinicum, and Department of Medical and Clinical Genetics

Subjects
Cancer Research, SUSCEPTIBILITY ALLELES, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], QH426-470, Settore MED/03 - GENETICA MEDICA, Genoma humà, SUBTYPES, Breast cancer, 0302 clinical medicine, Risk Factors, CDKN2A, Genotype, BRCA2 MUTATION CARRIERS, Malalties hereditàries, GWAS, skin and connective tissue diseases, Genetics (clinical), POPULATION, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, COMMON VARIANTS, genetic modifiers, BRCA2, cancer risk, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, Genetic diseases, Adult, Heterozygote, Medizinische Fakultät -ohne weitere Spezifikation, education, Population, Breast Neoplasms, Single-nucleotide polymorphism, Locus (genetics), Human chromosomes, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, BRCA2-specific modifier locus at 6p24, Càncer de mama, 03 medical and health sciences, TRANSCRIPTION FACTOR AP-2, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Allele, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, BRCA2 Protein, Cromosomes humans, Human genome, Hereditary cancer and cancer-related syndromes [ONCOL 1], CONSORTIUM, medicine.disease, Mutation, 3111 Biomedicine, ZNF365, Genome-Wide Association Study
Abstract

Contains fulltext : 118578.pdf (Publisher’s version ) (Open Access) Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013

39. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

Author

Couch, Fergus J, Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B, Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M, Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M, Lee, Adam, Bacot, François, Vincent, Daniel, Hogervorst, Frans BL, Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, kConFab Investigators, Radice, Paolo, Schmutzler, Rita Katharina, SWE-BRCA, Domchek, Susan M, Piedmonte, Marion, Singer, Christian F, Friedman, Eitan, Thomassen, Mads, Ontario Cancer Genetics Network, Hansen, Thomas VO, Neuhausen, Susan L, Szabo, Csilla I, Blanco, Ignacio, Greene, Mark H, Karlan, Beth Y, Garber, Judy, Phelan, Catherine M, Weitzel, Jeffrey N, Montagna, Marco, Olah, Edith, Andrulis, Irene L, Godwin, Andrew K, Yannoukakos, Drakoulis, Goldgar, David E, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B, van Rensburg, Elizabeth J, Hamann, Ute, Ramus, Susan J, Toland, Amanda Ewart, Caligo, Maria A, Olopade, Olufunmilayo I, Tung, Nadine, Claes, Kathleen, Beattie, Mary S, Southey, Melissa C, Imyanitov, Evgeny N, Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M, Kwong, Ava, Diez, Orland, Balmaña, Judith, Barkardottir, Rosa B, Arun, Banu K, Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A, Campbell, Ian, van der Hout, Annemarie H, van Deurzen, Carolien HM, Seynaeve, Caroline, Gómez Garcia, Encarna B, van Leeuwen, Flora E, Meijers-Heijboer, Hanne EJ, Gille, Johannes JP, Ausems, Margreet GEM, Blok, Marinus J, Ligtenberg, Marjolijn JL, Rookus, Matti A, Devilee, Peter, Verhoef, Senno, van Os, Theo AM, Wijnen, Juul T, HEBON, EMBRACE, Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D Gareth, Izatt, Louise, Eeles, Rosalind A, Adlard, Julian, and Hunter, Kent W

Subjects
Heterozygote, endocrine system diseases, Genotype, Breast Neoplasms, EMBRACE, GEMO Study Collaborators, Rare Diseases, Risk Factors, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Polymorphism, skin and connective tissue diseases, HEBON, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Human Genome, BCFR, Single Nucleotide, SWE-BRCA, Middle Aged, Prognosis, Ovarian Cancer, Mutation, kConFab Investigators, Female, CIMBA, Ontario Cancer Genetics Network, Genome-Wide Association Study, Developmental Biology
Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Published
2013

40. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042

Author

Milne, Roger L, Benítez, Javier, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Arias, José Ignacio, Zamora, M Pilar, Burwinkel, Barbara, Bartram, Claus R, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Southey, Melissa C, Smith, Letitia, Spurdle, Amanda B, Hopper, John L, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Dörk, Thilo, Devilee, Peter, van Asperen, Christie J, Tollenaar, Rob AEM, Seynaeve, Caroline, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Yuqing, Ahmed, Shahana, Dunning, Alison M, Maranian, Melanie, Pharoah, Paul DP, Chenevix-Trench, Georgia, Beesley, Jonathan, kConFab Investigators, AOCS Group, Bogdanova, Natalia V, Antonenkova, Natalia N, Zalutsky, Iosif V, Anton-Culver, Hoda, Ziogas, Argyrios, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, Haas, Susanne, Fasching, Peter A, Strick, Reiner, Ekici, Arif B, Beckmann, Matthias W, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, English, Dallas R, Fletcher, Olivia, Johnson, Nichola, dos Santos Silva, Isabel, Peto, Julian, Turnbull, Clare, Hines, Sarah, Renwick, Anthony, Rahman, Nazneen, Nordestgaard, Børge G, Bojesen, Stig E, Flyger, Henrik, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, García-Closas, Montserrat, Chanock, Stephen, Lissowska, Jolanta, Brinton, Louise A, Chang-Claude, Jenny, Wang-Gohrke, Shan, Shen, Chen-Yang, Wang, Hui-Chun, Yu, Jyh-Cherng, Chen, Sou-Tong, Bermisheva, Marina, Nikolaeva, Tatjana, Khusnutdinova, Elza, Humphreys, Manjeet K, Morrison, Jonathan, Platte, Radka, Easton, Douglas F, and Breast Cancer Association Consortium

Subjects
Adult, Asian Continental Ancestry Group, Neoplasms, Hormone-Dependent, Genotype, European Continental Ancestry Group, Oncology and Carcinogenesis, Breast Neoplasms, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Gene Frequency, Confidence Intervals, Odds Ratio, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aged, Carcinoma, Ductal, Breast, AOCS Group, Middle Aged, Confounding Factors (Epidemiology), Carcinoma, Intraductal, Noninfiltrating, Receptors, Estrogen, Case-Control Studies, Breast Cancer Association Consortium, kConFab Investigators, Female, Receptors, Progesterone
Abstract

A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P(trend) = 1.0 x 10(-19)). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P > or = .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10(-15)) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10(-14)) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

Published
2009

41. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Antoniou, Antonis C, Sinilnikova, Olga M, McGuffog, Lesley, Healey, Sue, Nevanlinna, Heli, Heikkinen, Tuomas, Simard, Jacques, Spurdle, Amanda B, Beesley, Jonathan, Chen, Xiaoqing, Kathleen Cuningham Foundation Consortium, for Research into Familial Breast Cancer, Neuhausen, Susan L, Ding, Yuan C, Couch, Fergus J, Wang, Xianshu, Fredericksen, Zachary, Peterlongo, Paolo, Peissel, Bernard, Bonanni, Bernardo, Viel, Alessandra, Bernard, Loris, Radice, Paolo, Szabo, Csilla I, Foretova, Lenka, Zikan, Michal, Claes, Kathleen, Greene, Mark H, Mai, Phuong L, Rennert, Gad, Lejbkowicz, Flavio, Andrulis, Irene L, Ozcelik, Hilmi, Glendon, Gord, Group, OCGN, Gerdes, Anne-Marie, Thomassen, Mads, Sunde, Lone, Caligo, Maria A, Laitman, Yael, Kontorovich, Tair, Cohen, Shimrit, Kaufman, Bella, Dagan, Efrat, Baruch, Ruth Gershoni, Friedman, Eitan, Harbst, Katja, Barbany-Bustinza, Gisela, Rantala, Johanna, Ehrencrona, Hans, Karlsson, Per, Domchek, Susan M, Nathanson, Katherine L, Osorio, Ana, Blanco, Ignacio, Lasa, Adriana, Benítez, Javier, Hamann, Ute, Hogervorst, Frans B L, Rookus, Matti A, Collee, J Margriet, Devilee, Peter, Ligtenberg, Marjolijn J, van der Luijt, Rob B, Aalfs, Cora M, Waisfisz, Quinten, Wijnen, Juul, van Roozendaal, Cornelis E P, Group, HEBON, Peock, Susan, Cook, Margaret, Frost, Debra, Oliver, Clare, Platte, Radka, Evans, D Gareth, Lalloo, Fiona, Eeles, Rosalind, Izatt, Louise, Davidson, Rosemarie, Chu, Carol, Eccles, Diana, Cole, Trevor, Hodgson, Shirley, Group, EMBRACE, Godwin, Andrew K, Stoppa-Lyonnet, Dominique, Buecher, Bruno, Léoné, Mélanie, Bressac-de Paillerets, Brigitte, Remenieras, Audrey, Caron, Olivier, Lenoir, Gilbert M, Sevenet, Nicolas, Longy, Michel, Ferrer, Sandra Fert, Prieur, Fabienne, Group, GEMO, Goldgar, David, Miron, Alexander, John, Esther M, Buys, Saundra S, Daly, Mary B, Hopper, John L, Terry, Mary Beth, Yassin, Yosuf, Family Registry, Breast Cancer, Singer, Christian, Gschwantler-Kaulich, Daphne, Staudigl, Christine, Hansen, Thomas v O, Barkardottir, Rosa Bjork, Kirchhoff, Tomas, Pal, Prodipto, Kosarin, Kristi, Offit, Kenneth, Piedmonte, Marion, Rodriguez, Gustavo C, Wakeley, Katie, Boggess, John F, Basil, Jack, Schwartz, Peter E, Blank, Stephanie V, Toland, Amanda E, Montagna, Marco, Casella, Cinzia, Imyanitov, Evgeny N, Allavena, Anna, Schmutzler, Rita K, Versmold, Beatrix, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Niederacher, Dieter, Deissler, Helmut, Fiebig, Britta, Suttner, Christian, Schönbuchner, Ines, Gadzicki, Dorothea, Caldes, Trinidad, de la Hoya, Miguel, Pooley, Karen A, Easton, Douglas F, Chenevix-Trench, Georgia, Group, CIMBA, University of Groningen, Human genetics, CCA - Oncogenesis, and Human Genetics

Subjects
endocrine system diseases, SUSCEPTIBILITY, 0302 clinical medicine, skin and connective tissue diseases, POPULATION, Genetics (clinical), Aged, 80 and over, 0303 health sciences, education.field_of_study, BRCA1 Protein, Association Studies Articles, Microfilament Proteins, General Medicine, Middle Aged, 3. Good health, Chromosomes, Human, Pair 2, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, Breast disease, Chromosomes, Human, Pair 8, Adult, EXPRESSION, Heterozygote, Population, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, Young Adult, 03 medical and health sciences, Breast cancer, Translational research [ONCOL 3], Genetics, medicine, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Aged, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], Genetic Variation, Cancer, Odds ratio, ALLELES, medicine.disease, GENE, Minor allele frequency, Genetics, Population, ESTROGEN-RECEPTOR, Mutation, Cancer research, Follow-Up Studies, Genome-Wide Association Study
Abstract

Contains fulltext : 81601.pdf (Publisher’s version ) (Closed access) Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Published
2009

42. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author

Blein, Sophie, Bardel, Claire, Danjean, Vincent, McGuffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B, Soucy, Penny, Terry, Mary Beth, Chung, Wendy K, Goldgar, David E, Buys, Saundra S, Breast Cancer Family Registry, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, Van Rensburg, Elizabeth J, Neuhausen, Susan L, Ding, Yuan Chun, Gerdes, Anne-Marie, Ejlertsen, Bent, Nielsen, Finn C, Hansen, Thomas Vo, Osorio, Ana, Benitez, Javier, Conejero, Raquel Andrés, Segota, Ena, Weitzel, Jeffrey N, Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L, Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Tischkowitz, Marc, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K, Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Schmutzler, Rita K, Preisler-Adams, Sabine, Markov, Nadja Bogdanova, Wang-Gohrke, Shan, De Pauw, Antoine, Lefol, Cédrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, GEMO Study Collaborators, Dreyfus, Hélène, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valérie, Sornin, Valérie, Bignon, Yves-Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, DiSilvestro, Paul A, De La Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Jager, Agnes, Van Den Ouweland, Ans Mw, Kets, Carolien M, Aalfs, Cora M, Van Leeuwen, Flora E, Hogervorst, Frans Bl, Meijers-Heijboer, Hanne Ej, HEBON, Oosterwijk, Jan C, Van Roozendaal, Kees Ep, Rookus, Matti A, Devilee, Peter, Van Der Luijt, Rob B, Olah, Edith, Diez, Orland, Teulé, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesús, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Agnarsson, Bjarni A, Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R, Spurdle, Amanda B, Foulkes, William, Olswold, Curtis, Lindor, Noralane M, Pankratz, Vernon S, Szabo, Csilla I, Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F, Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Greene, Mark H, Mai, Phuong L, Rennert, Gad, Imyanitov, Evgeny N, Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L, Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A, Jensen, Uffe Birk, Caligo, Maria A, Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I, Nussbaum, Robert L, Ramus, Susan J, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Arun, Banu K, Mitchell, Gillian, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Stoppa-Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J, Offit, Kenneth, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Mazoyer, Sylvie, Phelan, Catherine M, Sinilnikova, Olga M, and Cox, David G

Subjects
Risk, Heterozygote, Genes, Mitochondrial, Haplotypes, BRCA1 Protein, Genes, BRCA2, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Phylogeny, 3. Good health
Abstract

INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

43. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author

Kuchenbaecker, Karoline B, Neuhausen, Susan L, Robson, Mark, Barrowdale, Daniel, McGuffog, Lesley, Mulligan, Anna Marie, Andrulis, Irene L, Spurdle, Amanda B, Schmidt, Marjanka K, Schmutzler, Rita K, Engel, Christoph, Wappenschmidt, Barbara, Nevanlinna, Heli, Thomassen, Mads, Southey, Melissa, Radice, Paolo, Ramus, Susan J, Domchek, Susan M, Nathanson, Katherine L, Lee, Andrew, Healey, Sue, Nussbaum, Robert L, Rebbeck, Timothy R, Arun, Banu K, James, Paul, Karlan, Beth Y, Lester, Jenny, Cass, Ilana, Breast Cancer Family Registry, the, Terry, Mary Beth, Daly, Mary B, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, v O Hansen, Thomas, Ejlertsen, Bent, Gerdes, Anne-Marie, Nielsen, Finn C, Dennis, Joe, Cunningham, Julie, Hart, Steven, Slager, Susan, Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N, Tafur, Isaac, Hander, Mary, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Roversi, Gaia, Scuvera, Giulietta, Bonanni, Bernardo, Mariani, Paolo, Volorio, Sara, Dolcetti, Riccardo, Varesco, Liliana, Papi, Laura, Tibiletti, Maria Grazia, Giannini, Giuseppe, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE Study, the, Douglas, Fiona, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Ong, Kai-ren, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Ellis, Steve, Godwin, Andrew K, Rhiem, Kerstin, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Steinemann, Doris, Bogdanova-Markov, Nadja, Kast, Karin, Varon-Mateeva, Raymonda, Wang-Gohrke, Shan, Gehrig, Andrea, Markiefka, Birgid, Buecher, Bruno, Lefol, Cédrick, Stoppa-Lyonnet, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, GEMO Study Collaborators, the, Barjhoux, Laure, Faivre, Laurence, Longy, Michel, Sevenet, Nicolas, Sinilnikova, Olga M, Mazoyer, Sylvie, Bonadona, Valérie, Caux-Moncoutier, Virginie, Isaacs, Claudine, Van Maerken, Tom, Claes, Kathleen, Piedmonte, Marion, Andrews, Lesley, Hays, John, Rodriguez, Gustavo C, Caldes, Trinidad, de la Hoya, Miguel, Khan, Sofia, Hogervorst, Frans BL, Aalfs, Cora M, de Lange, JL, Meijers-Heijboer, Hanne EJ, van der Hout, Annemarie H, Wijnen, Juul T, van Roozendaal, KEP, Mensenkamp, Arjen R, van den Ouweland, Ans MW, van Deurzen, Carolien HM, van der Luijt, Rob B, HEBON, ., Olah, Edith, Diez, Orland, Lazaro, Conxi, Blanco, Ignacio, Teulé, Alex, Menendez, Mireia, Jakubowska, Anna, Lubinski, Jan, Cybulski, Cezary, Gronwald, Jacek, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Arason, Adalgeir, Maugard, Christine, Soucy, Penny, Montagna, Marco, Agata, Simona, Teixeira, Manuel R, KConFab Investigators, the, Olswold, Curtis, Lindor, Noralane, Pankratz, Vernon S, Hallberg, Emily, Wang, Xianshu, Szabo, Csilla I, Vijai, Joseph, Jacobs, Lauren, Corines, Marina, Lincoln, Anne, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F, Rappaport, Christine, Gschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Phelan, Catherine M, Mai, Phuong L, Greene, Mark H, Rennert, Gad, Imyanitov, Evgeny N, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Jensen, Uffe Birk, Caligo, Maria A, Friedman, Eitan, Berger, Raanan, Laitman, Yael, Rantala, Johanna, Arver, Brita, Loman, Niklas, Borg, Ake, Ehrencrona, Hans, Olopade, Olufunmilayo I, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Offit, Kenneth, Couch, Fergus J, Antoniou, Antonis C, CIMBA, on behalf of, Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, Receptor, ErbB-2, Genes, BRCA2, BRCA, LOCI, Genes, BRCA1, MODIFIERS, VARIANTS, ErbB-2, 610 Medical sciences Medicine, Ductal, Receptors, Medicine and Health Sciences, INVESTIGATORS, Breast, skin and connective tissue diseases, Progesterone, Medicine(all), Carcinoma, Ductal, Breast, Middle Aged, Adult, Aged, Alleles, Breast Neoplasms, Carcinoma, Carcinoma, Lobular, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Neoplasm Grading, Neoplasm Staging, Receptors, Estrogen, Receptors, Progesterone, Oncology, TUMOR SUBTYPES, Receptor, Research Article, MEDULLARY CARCINOMA, OVARIAN-CANCER, Lobular, GENOME-WIDE ASSOCIATION, CONSORTIUM, BRCA1, Estrogen, BRCA2, ESTROGEN-RECEPTOR, Genes
Abstract

Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P

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44. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Barrowdale, V., DMulligan A. M., C, dEmail, Author, Neuhausen, eEmail Author, S. L., Fox, fEmail Author, S., Karlan, gEmail Author, B. Y., Mitchell G., H, iEmail, Author, James P., H, Thull, jEmail Author, D. L., Zorn, jEmail Author, K. K., Carter, kEmail Author, N. J., Nathanson, lEmail Author, K. L., Domchek, lEmail Author, S. M., Rebbeck, mEmail Author, T. R., Ramus, nEmail Author, S. J., Nussbaum, oEmail Author, R. L., Olopade, pEmail Author, O. I., Rantala, qEmail Author, J., Yoon, S. -Y., R, sEmail, Author, Caligo, tEmail Author, M. A., Spugnesi, tEmail Author, L., Bojesen, uEmail Author, A., Pedersen, vEmail Author, I. S., Thomassen, wEmail Author, M., Jensen, xEmail Author, U. B., Toland, yEmail Author, A. E., Senter, zEmail Author, L., Andrulis I. L., D, abEmail, Author, Glendon, aaEmail Author, G., Hulick, acEmail Author, P. J., Imyanitov, adEmail Author, E. N., Greene, aeEmail Author, M. H., Mai, aeEmail Author, P. L., Singer, afEmail Author, C. F., Rappaport-Fuerhauser, afEmail Author, C., Kramer, agEmail Author, G., Vijai, ahEmail Author, J., Offit, ahEmail Author, K., Robson, aiEmail Author, M., Lincoln, ahEmail Author, A., Jacobs, ahEmail Author, L., Machackova, ajEmail Author, E., Foretova, akEmail Author, L., Navratilova, ajEmail Author, M., Vasickova, ajEmail Author, P., Couch, F. J., Al, amEmail, Author, Hallberg, amEmail Author, E., Ruddy, anEmail Author, K. J., Sharma, aoEmail Author, P., Kim, apEmail Author, S. -W., Teixeira, M. R., Aq, arEmail, Author, Pinto, aqEmail Author, P., Montagna, asEmail Author, M., Matricardi, asEmail Author, L., Arason, atEmail Author, A., Johannsson, auEmail Author, O. T., Barkardottir, atEmail Author, R. B., Jakubowska, avEmail Author, A., Lubinski, avEmail Author, J., Izquierdo, awEmail Author, A., Pujana, axEmail Author, M. A., Balmaña, ayEmail Author, J., Diez, azEmail Author, O., Ivady, baEmail Author, G., Papp, bbEmail Author, J., Olah, bbEmail Author, E., Kwong, Bc, A., bdEmail, Author, Nevanlinna, beEmail Author, H., Aittomäki, bfEmail Author, K., Perez, Segura, bgEmail Author, P., Caldes, bhEmail Author, T., Van, Maerken, biEmail Author, T., Poppe, biEmail Author, B., Claes, biEmail Author, K. B. M., Isaacs, bjEmail Author, C., Elan, bkEmail Author, C., Lasset, Bl, C., bmEmail, Author, Stoppa-Lyonnet, Bk, D., bnEmail, Author, Barjhoux, boEmail Author, L., Belotti, bkEmail Author, M., Meindl, bpEmail Author, A., Gehrig, bqEmail Author, A., Sutter, brEmail Author, C., Engel, bsEmail Author, C., Niederacher, btEmail Author, D., Steinemann, buEmail Author, D., Hahnen, bvEmail Author, E., Kast, bwEmail Author, K., Arnold, bxEmail Author, N., Varon-Mateeva, byEmail Author, R., Wand, bzEmail Author, D., Godwin, caEmail Author, A. K., Evans, cbEmail Author, D. G., Frost, bEmail Author, D., Perkins, bEmail Author, J., Adlard, ccEmail Author, J., Izatt, cdEmail Author, L., Platte, ceEmail Author, R., Eeles, cfEmail Author, R., Ellis, bEmail Author, S., Hamann, cfEmail Author, U., Garber, cgEmail Author, J., Fostira, chEmail Author, F., Fountzilas, ciEmail Author, G., Pasini, Cj, B., ckEmail, Author, Giannini, aEmail Author, G., Rizzolo, aEmail Author, P., Russo, clEmail Author, A., Cortesi, cmEmail Author, L., Papi, Laura, cnEmail Author, L., Varesco, coEmail Author, L., Palli, cpEmail Author, D., Zanna, cpEmail Author, I., Savarese, cqEmail Author, A., Radice, crEmail Author, P., Manoukian, csEmail Author, S., Peissel, csEmail Author, B., Barile, ctEmail Author, M., Bonanni, ctEmail Author, B., Viel, cuEmail Author, A., Pensotti, Cv, V., cwEmail, Author, Tommasi, cxEmail Author, S., Peterlongo, cvEmail Author, P., Weitzel, cyEmail Author, J. N., Osorio, Cz, A., daEmail, Author, Benitez, Da, J., dcEmail, Author, McGuffog, bEmail Author, L., Healey, ddEmail Author, S., Gerdes, deEmail Author, A. -M., Ejlertsen, dfEmail Author, B., Hansen, dgEmail Author, T. V. O., Steele, eEmail Author, L., Ding, eEmail Author, Y. C., Tung, dhEmail Author, N., Janavicius, diEmail Author, R., Goldgar, djEmail Author, D. E., Buys, dkEmail Author, S. S., Daly, dlEmail Author, M. B., Bane, dmEmail Author, A., Terry, dnEmail Author, M. B., John, doEmail Author, E. M., Southey, dpEmail Author, M., Easton, bEmail Author, D. F., Chenevix-Trench, ddEmail Author, G., Antoniou, bEmail Author, A. 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Subjects
Male, 0301 basic medicine, Genotype-phenotype correlation, Pathology, genotype-phenotype correlations, endocrine system diseases, Settore MED/06 - Oncologia Medica, FEATURES, male breast cancer, Genotype-phenotype correlations, Logistic regression, Histologic grade, 610 Medical sciences Medicine, Breast cancer, 0302 clinical medicine, Epidemiology, Medicine and Health Sciences, polycyclic compounds, skin and connective tissue diseases, POPULATION, RISK, education.field_of_study, BRCA1 Protein, Men, Single Nucleotide, Middle Aged, 3. Good health, GRADE, 030220 oncology & carcinogenesis, Male breast cancer, oncology, Female, Breast Neoplasm, Research Article, Human, Adult, medicine.medical_specialty, CARCINOMA, Genotype–phenotype correlations, 3122 Cancers, Population, Breast Neoplasms, BRCA1/2, histologic grade, pathology, cancer research, Male breast cancer, BRCA1, BRCA2, Polymorphism, Single Nucleotide, Càncer de mama, Breast Neoplasms, Male, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Journal Article, Carcinoma, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, education, Aged, Neoplasm Staging, BRCA2 Protein, business.industry, Odds ratio, medicine.disease, Confidence interval, 030104 developmental biology, ddc:161, Homes, Mutation, Oncology, Cancer Research, business
Abstract

Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0671-y) contains supplementary material, which is available to authorized users.

Published
2016

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