Author: "Stegmaier C." / Topic: genetic predisposition to disease - Searchworks@Jio Institute Digital Library Search Results

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32 results on '"Stegmaier C."'

1. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Author: Mavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A, Tyrer JP, Chen TH, Wang Q, Bolla MK, Yang X, Adank MA, Ahearn T, Aittomäki K, Allen J, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Auer PL, Auvinen P, Barrdahl M, Beane Freeman LE, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brauch H, Bremer M, Brenner H, Brentnall A, Brock IW, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Campa D, Carter BD, Castelao JE, Chanock SJ, Chlebowski R, Christiansen H, Clarke CL, Collée JM, Cordina-Duverger E, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Engel C, Eriksson M, Evans DG, Fasching PA, Figueroa J, Fletcher O, Flyger H, Försti A, Fritschi L, Gabrielson M, Gago-Dominguez M, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Gilyazova IR, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hankinson SE, Harkness EF, Hart SN, He W, Hein A, Heyworth J, Hillemanns P, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huang G, Humphreys K, Hunter DJ, Jakimovska M, Jakubowska A, Janni W, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kaczmarek K, Kataja V, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Knight JA, Ko YD, Kosma VM, Koutros S, Kristensen VN, Krüger U, Kühl T, Lambrechts D, Le Marchand L, Lee E, Lejbkowicz F, Lilyquist J, Lindblom A, Lindström S, Lissowska J, Lo WY, Loibl S, Long J, Lubiński J, Lux MP, MacInnis RJ, Maishman T, Makalic E, Maleva Kostovska I, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Martinez ME, Mavroudis D, McLean C, Meindl A, Menon U, Middha P, Miller N, Moreno F, Mulligan AM, Mulot C, Muñoz-Garzon VM, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen SF, Nordestgaard BG, Norman A, Offit K, Olson JE, Olsson H, Orr N, Pankratz VS, Park-Simon TW, Perez JIA, Pérez-Barrios C, Peterlongo P, Peto J, Pinchev M, Plaseska-Karanfilska D, Polley EC, Prentice R, Presneau N, Prokofyeva D, Purrington K, Pylkäs K, Rack B, Radice P, Rau-Murthy R, Rennert G, Rennert HS, Rhenius V, Robson M, Romero A, Ruddy KJ, Ruebner M, Saloustros E, Sandler DP, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seynaeve C, Shah M, Sherman ME, Shrubsole MJ, Shu XO, Slager S, Smeets A, Sohn C, Soucy P, Southey MC, Spinelli JJ, Stegmaier C, Stone J, Swerdlow AJ, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Thöne K, Tollenaar RAEM, Tomlinson I, Truong T, Tzardi M, Ulmer HU, Untch M, Vachon CM, van Veen EM, Vijai J, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zhang Y, Zheng W, Ziogas A, Dunning AM, Thompson DJ, Chenevix-Trench G, Chang-Claude J, Schmidt MK, Hall P, Milne RL, Pharoah PDP, Antoniou AC, Chatterjee N, Kraft P, García-Closas M, Simard J, and Easton DF
Subjects: Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms diagnosis, Breast Neoplasms prevention & control, Female, Humans, Medical History Taking, Middle Aged, Polymorphism, Single Nucleotide genetics, Receptors, Estrogen metabolism, Reproducibility of Results, Risk Assessment, Breast Neoplasms classification, Breast Neoplasms genetics, Genetic Predisposition to Disease, Multifactorial Inheritance genetics
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2019
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2. Discovery of common and rare genetic risk variants for colorectal cancer.

Author: Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, Conti DV, Qu C, Jeon J, Edlund CK, Greenside P, Wainberg M, Schumacher FR, Smith JD, Levine DM, Nelson SC, Sinnott-Armstrong NA, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Bamia C, Banbury BL, Baron JA, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Chirlaque MD, Cho SH, Connolly CM, Cross AJ, Cuk K, Curtis KR, de la Chapelle A, Doheny KF, Duggan D, Easton DF, Elias SG, Elliott F, English DR, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Forman D, Gala M, Gallinger S, Gauderman WJ, Giles GG, Gillanders E, Gong J, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hampel H, Harlid S, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Hunter DJ, Ibañez-Sanz G, Idos GE, Ingersoll R, Jackson RD, Jacobs EJ, Jenkins MA, Joshi AD, Joshu CE, Keku TO, Key TJ, Kim HR, Kobayashi E, Kolonel LN, Kooperberg C, Kühn T, Küry S, Kweon SS, Larsson SC, Laurie CA, Le Marchand L, Leal SM, Lee SC, Lejbkowicz F, Lemire M, Li CI, Li L, Lieb W, Lin Y, Lindblom A, Lindor NM, Ling H, Louie TL, Männistö S, Markowitz SD, Martín V, Masala G, McNeil CE, Melas M, Milne RL, Moreno L, Murphy N, Myte R, Naccarati A, Newcomb PA, Offit K, Ogino S, Onland-Moret NC, Pardini B, Parfrey PS, Pearlman R, Perduca V, Pharoah PDP, Pinchev M, Platz EA, Prentice RL, Pugh E, Raskin L, Rennert G, Rennert HS, Riboli E, Rodríguez-Barranco M, Romm J, Sakoda LC, Schafmayer C, Schoen RE, Seminara D, Shah M, Shelford T, Shin MH, Shulman K, Sieri S, Slattery ML, Southey MC, Stadler ZK, Stegmaier C, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Thomas SS, Toland AE, Trichopoulou A, Ulrich CM, Van Den Berg DJ, van Duijnhoven FJB, Van Guelpen B, van Kranen H, Vijai J, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Win AK, Wolf CR, Wolk A, Woods MO, Wu AH, Zaidi SH, Zanke BW, Zhang Q, Zheng W, Scacheri PC, Potter JD, Bassik MC, Kundaje A, Casey G, Moreno V, Abecasis GR, Nickerson DA, Gruber SB, Hsu L, and Peters U
Subjects: Aged, Case-Control Studies, Female, Genome-Wide Association Study methods, Genotype, Humans, Male, Middle Aged, RNA, Long Noncoding genetics, Risk Factors, Signal Transduction genetics, Colorectal Neoplasms genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 -8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
Published: 2019
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3. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Author: Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, Jiang X, Rostamianfar A, Finucane H, Bolla MK, McGuffog L, Wang Q, Aalfs CM, Adams M, Adlard J, Agata S, Ahmed S, Ahsan H, Aittomäki K, Al-Ejeh F, Allen J, Ambrosone CB, Amos CI, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Auber B, Auer PL, Ausems MGEM, Azzollini J, Bacot F, Balmaña J, Barile M, Barjhoux L, Barkardottir RB, Barrdahl M, Barnes D, Barrowdale D, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Bernstein L, Bignon YJ, Blazer KR, Blok MJ, Blomqvist C, Blot W, Bobolis K, Boeckx B, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Børresen-Dale AL, Bozsik A, Bradbury AR, Brand JS, Brauch H, Brenner H, Bressac-de Paillerets B, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Brunet J, Brüning T, Burwinkel B, Buys SS, Byun J, Cai Q, Caldés T, Caligo MA, Campbell I, Canzian F, Caron O, Carracedo A, Carter BD, Castelao JE, Castera L, Caux-Moncoutier V, Chan SB, Chang-Claude J, Chanock SJ, Chen X, Cheng TD, Chiquette J, Christiansen H, Claes KBM, Clarke CL, Conner T, Conroy DM, Cook J, Cordina-Duverger E, Cornelissen S, Coupier I, Cox A, Cox DG, Cross SS, Cuk K, Cunningham JM, Czene K, Daly MB, Damiola F, Darabi H, Davidson R, De Leeneer K, Devilee P, Dicks E, Diez O, Ding YC, Ditsch N, Doheny KF, Domchek SM, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dubois S, Dugué PA, Dumont M, Dunning AM, Durcan L, Dwek M, Dworniczak B, Eccles D, Eeles R, Ehrencrona H, Eilber U, Ejlertsen B, Ekici AB, Eliassen AH, Engel C, Eriksson M, Fachal L, Faivre L, Fasching PA, Faust U, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gaddam P, Gammon MD, Ganz PA, Gapstur SM, Garber J, Garcia-Barberan V, García-Sáenz JA, Gaudet MM, Gauthier-Villars M, Gehrig A, Georgoulias V, Gerdes AM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goodfellow P, Greene MH, Alnæs GIG, Grip M, Gronwald J, Grundy A, Gschwantler-Kaulich D, Guénel P, Guo Q, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hallberg E, Hamann U, Hamel N, Hankinson S, Hansen TVO, Harrington P, Hart SN, Hartikainen JM, Healey CS, Hein A, Helbig S, Henderson A, Heyworth J, Hicks B, Hillemanns P, Hodgson S, Hogervorst FB, Hollestelle A, Hooning MJ, Hoover B, Hopper JL, Hu C, Huang G, Hulick PJ, Humphreys K, Hunter DJ, Imyanitov EN, Isaacs C, Iwasaki M, Izatt L, Jakubowska A, James P, Janavicius R, Janni W, Jensen UB, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kast K, Keeman R, Kerin MJ, Kets CM, Keupers M, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Konstantopoulou I, Kosma VM, Kristensen VN, Kruse TA, Kwong A, Lænkholm AV, Laitman Y, Lalloo F, Lambrechts D, Landsman K, Lasset C, Lazaro C, Le Marchand L, Lecarpentier J, Lee A, Lee E, Lee JW, Lee MH, Lejbkowicz F, Lesueur F, Li J, Lilyquist J, Lincoln A, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Loud JT, Lubinski J, Luccarini C, Lush M, MacInnis RJ, Maishman T, Makalic E, Kostovska IM, Malone KE, Manoukian S, Manson JE, Margolin S, Martens JWM, Martinez ME, Matsuo K, Mavroudis D, Mazoyer S, McLean C, Meijers-Heijboer H, Menéndez P, Meyer J, Miao H, Miller A, Miller N, Mitchell G, Montagna M, Muir K, Mulligan AM, Mulot C, Nadesan S, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Niederacher D, Nielsen SF, Nordestgaard BG, Norman A, Nussbaum RL, Olah E, Olopade OI, Olson JE, Olswold C, Ong KR, Oosterwijk JC, Orr N, Osorio A, Pankratz VS, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Lloyd R, Pedersen IS, Peissel B, Peixoto A, Perez JIA, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Pinchev M, Plaseska-Karanfilska D, Poppe B, Porteous ME, Prentice R, Presneau N, Prokofieva D, Pugh E, Pujana MA, Pylkäs K, Rack B, Radice P, Rahman N, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rennert HS, Rhenius V, Rhiem K, Richardson A, Rodriguez GC, Romero A, Romm J, Rookus MA, Rudolph A, Ruediger T, Saloustros E, Sanders J, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seal S, Senter L, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng X, Shimelis H, Shrubsole MJ, Shu XO, Side LE, Singer CF, Sohn C, Southey MC, Spinelli JJ, Spurdle AB, Stegmaier C, Stoppa-Lyonnet D, Sukiennicki G, Surowy H, Sutter C, Swerdlow A, Szabo CI, Tamimi RM, Tan YY, Taylor JA, Tejada MI, Tengström M, Teo SH, Terry MB, Tessier DC, Teulé A, Thöne K, Thull DL, Tibiletti MG, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Tranchant M, Truong T, Tucker K, Tung N, Tyrer J, Ulmer HU, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van Rensburg EJ, Varesco L, Varon-Mateeva R, Vega A, Viel A, Vijai J, Vincent D, Vollenweider J, Walker L, Wang Z, Wang-Gohrke S, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wesseling J, Whittemore AS, Wijnen JT, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yang XR, Yannoukakos D, Zaffaroni D, Zheng W, Zhu B, Ziogas A, Ziv E, Zorn KK, Gago-Dominguez M, Mannermaa A, Olsson H, Teixeira MR, Stone J, Offit K, Ottini L, Park SK, Thomassen M, Hall P, Meindl A, Schmutzler RK, Droit A, Bader GD, Pharoah PDP, Couch FJ, Easton DF, Kraft P, Chenevix-Trench G, García-Closas M, Schmidt MK, Antoniou AC, and Simard J
Subjects: Breast Neoplasms ethnology, Breast Neoplasms metabolism, Female, Genetic Predisposition to Disease ethnology, Genome-Wide Association Study methods, Heterozygote, Humans, Receptors, Estrogen metabolism, Risk Factors, White People genetics, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Mutation, Polymorphism, Single Nucleotide
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Published: 2017
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4. Association analysis identifies 65 new breast cancer risk loci.

Author: Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, Lemaçon A, Soucy P, Glubb D, Rostamianfar A, Bolla MK, Wang Q, Tyrer J, Dicks E, Lee A, Wang Z, Allen J, Keeman R, Eilber U, French JD, Qing Chen X, Fachal L, McCue K, McCart Reed AE, Ghoussaini M, Carroll JS, Jiang X, Finucane H, Adams M, Adank MA, Ahsan H, Aittomäki K, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Arun B, Auer PL, Bacot F, Barrdahl M, Baynes C, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Brinton L, Broberg P, Brock IW, Broeks A, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Butterbach K, Cai Q, Cai H, Caldés T, Canzian F, Carracedo A, Carter BD, Castelao JE, Chan TL, David Cheng TY, Seng Chia K, Choi JY, Christiansen H, Clarke CL, Collée M, Conroy DM, Cordina-Duverger E, Cornelissen S, Cox DG, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Elvira M, Engel C, Eriksson M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gaborieau V, Gabrielson M, Gago-Dominguez M, Gao YT, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hamel N, Hankinson S, Harrington P, Hart SN, Hartikainen JM, Hartman M, Hein A, Heyworth J, Hicks B, Hillemanns P, Ho DN, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Hou MF, Hsiung CN, Huang G, Humphreys K, Ishiguro J, Ito H, Iwasaki M, Iwata H, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kasuga Y, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Kosma VM, Kristensen VN, Krüger U, Kwong A, Lambrechts D, Le Marchand L, Lee E, Lee MH, Lee JW, Neng Lee C, Lejbkowicz F, Li J, Lilyquist J, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Lophatananon A, Lubinski J, Luccarini C, Lux MP, Ma ESK, MacInnis RJ, Maishman T, Makalic E, Malone KE, Kostovska IM, Mannermaa A, Manoukian S, Manson JE, Margolin S, Mariapun S, Martinez ME, Matsuo K, Mavroudis D, McKay J, McLean C, Meijers-Heijboer H, Meindl A, Menéndez P, Menon U, Meyer J, Miao H, Miller N, Taib NAM, Muir K, Mulligan AM, Mulot C, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Noh DY, Nordestgaard BG, Norman A, Olopade OI, Olson JE, Olsson H, Olswold C, Orr N, Pankratz VS, Park SK, Park-Simon TW, Lloyd R, Perez JIA, Peterlongo P, Peto J, Phillips KA, Pinchev M, Plaseska-Karanfilska D, Prentice R, Presneau N, Prokofyeva D, Pugh E, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Ruddy KJ, Rüdiger T, Rudolph A, Ruebner M, Rutgers EJT, Saloustros E, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Scott RJ, Scott C, Seal S, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng G, Sherman ME, Shrubsole MJ, Shu XO, Smeets A, Sohn C, Southey MC, Spinelli JJ, Stegmaier C, Stewart-Brown S, Stone J, Stram DO, Surowy H, Swerdlow A, Tamimi R, Taylor JA, Tengström M, Teo SH, Beth Terry M, Tessier DC, Thanasitthichai S, Thöne K, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Truong T, Tseng CC, Tsugane S, Ulmer HU, Ursin G, Untch M, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van der Kolk L, van der Luijt RB, Vincent D, Vollenweider J, Waisfisz Q, Wang-Gohrke S, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yamaji T, Yang XR, Har Yip C, Yoo KY, Yu JC, Zheng W, Zheng Y, Zhu B, Ziogas A, Ziv E, Lakhani SR, Antoniou AC, Droit A, Andrulis IL, Amos CI, Couch FJ, Pharoah PDP, Chang-Claude J, Hall P, Hunter DJ, Milne RL, García-Closas M, Schmidt MK, Chanock SJ, Dunning AM, Edwards SL, Bader GD, Chenevix-Trench G, Simard J, Kraft P, and Easton DF
Subjects: Asia ethnology, Asian People genetics, Binding Sites genetics, Breast Neoplasms diagnosis, Computer Simulation, Europe ethnology, Female, Humans, Multifactorial Inheritance genetics, Polymorphism, Single Nucleotide genetics, Regulatory Sequences, Nucleic Acid, Risk Assessment, Transcription Factors metabolism, White People genetics, Breast Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
Published: 2017
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5. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Author: Southey MC, Goldgar DE, Winqvist R, Pylkäs K, Couch F, Tischkowitz M, Foulkes WD, Dennis J, Michailidou K, van Rensburg EJ, Heikkinen T, Nevanlinna H, Hopper JL, Dörk T, Claes KB, Reis-Filho J, Teo ZL, Radice P, Catucci I, Peterlongo P, Tsimiklis H, Odefrey FA, Dowty JG, Schmidt MK, Broeks A, Hogervorst FB, Verhoef S, Carpenter J, Clarke C, Scott RJ, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Peto J, Dos-Santos-Silva I, Fletcher O, Johnson N, Bolla MK, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Burwinkel B, Yang R, Guénel P, Truong T, Menegaux F, Sanchez M, Bojesen S, Nielsen SF, Flyger H, Benitez J, Zamora MP, Perez JI, Menéndez P, Anton-Culver H, Neuhausen S, Ziogas A, Clarke CA, Brenner H, Arndt V, Stegmaier C, Brauch H, Brüning T, Ko YD, Muranen TA, Aittomäki K, Blomqvist C, Bogdanova NV, Antonenkova NN, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Spurdle AB, Investigators K, Wauters E, Smeets D, Beuselinck B, Floris G, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Olson JE, Vachon C, Pankratz VS, McLean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Kristensen V, Alnæs GG, Zheng W, Hunter DJ, Lindstrom S, Hankinson SE, Kraft P, Andrulis I, Knight JA, Glendon G, Mulligan AM, Jukkola-Vuorinen A, Grip M, Kauppila S, Devilee P, Tollenaar RA, Seynaeve C, Hollestelle A, Garcia-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Darabi H, Eriksson M, Eccles DM, Rafiq S, Tapper WJ, Gerty SM, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Brand JS, Humphreys K, Cox A, Reed MW, Luccarini C, Baynes C, Dunning AM, Hamann U, Torres D, Ulmer HU, Rüdiger T, Jakubowska A, Lubinski J, Jaworska K, Durda K, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Swerdlow A, Ashworth A, Orr N, Jones M, González-Neira A, Pita G, Alonso MR, Álvarez N, Herrero D, Tessier DC, Vincent D, Bacot F, Simard J, Dumont M, Soucy P, Eeles R, Muir K, Wiklund F, Gronberg H, Schleutker J, Nordestgaard BG, Weischer M, Travis RC, Neal D, Donovan JL, Hamdy FC, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Schaid DJ, Kelley JL, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Butterbach K, Park J, Kaneva R, Batra J, Teixeira MR, Kote-Jarai Z, Olama AA, Benlloch S, Renner SP, Hartmann A, Hein A, Ruebner M, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Lambretchs S, Doherty JA, Rossing MA, Nickels S, Eilber U, Wang-Gohrke S, Odunsi K, Sucheston-Campbell LE, Friel G, Lurie G, Killeen JL, Wilkens LR, Goodman MT, Runnebaum I, Hillemanns PA, Pelttari LM, Butzow R, Modugno F, Edwards RP, Ness RB, Moysich KB, du Bois A, Heitz F, Harter P, Kommoss S, Karlan BY, Walsh C, Lester J, Jensen A, Kjaer SK, Høgdall E, Peissel B, Bonanni B, Bernard L, Goode EL, Fridley BL, Vierkant RA, Cunningham JM, Larson MC, Fogarty ZC, Kalli KR, Liang D, Lu KH, Hildebrandt MA, Wu X, Levine DA, Dao F, Bisogna M, Berchuck A, Iversen ES, Marks JR, Akushevich L, Cramer DW, Schildkraut J, Terry KL, Poole EM, Stampfer M, Tworoger SS, Bandera EV, Orlow I, Olson SH, Bjorge L, Salvesen HB, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Pejovic T, Bean Y, Brooks-Wilson A, Kelemen LE, Cook LS, Le ND, Górski B, Gronwald J, Menkiszak J, Høgdall CK, Lundvall L, Nedergaard L, Engelholm SA, Dicks E, Tyrer J, Campbell I, McNeish I, Paul J, Siddiqui N, Glasspool R, Whittemore AS, Rothstein JH, McGuire V, Sieh W, Cai H, Shu XO, Teten RT, Sutphen R, McLaughlin JR, Narod SA, Phelan CM, Monteiro AN, Fenstermacher D, Lin HY, Permuth JB, Sellers TA, Chen YA, Tsai YY, Chen Z, Gentry-Maharaj A, Gayther SA, Ramus SJ, Menon U, Wu AH, Pearce CL, Van Den Berg D, Pike MC, Dansonka-Mieszkowska A, Plisiecka-Halasa J, Moes-Sosnowska J, Kupryjanczyk J, Pharoah PD, Song H, Winship I, Chenevix-Trench G, Giles GG, Tavtigian SV, Easton DF, and Milne RL
Subjects: Breast Neoplasms epidemiology, Breast Neoplasms genetics, Case-Control Studies, Fanconi Anemia Complementation Group N Protein, Female, Genetic Association Studies, Humans, Male, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, Risk, Ataxia Telangiectasia Mutated Proteins genetics, Breast Neoplasms metabolism, Checkpoint Kinase 2 genetics, Genetic Predisposition to Disease, Mutation, Nuclear Proteins genetics, Prostatic Neoplasms metabolism, Tumor Suppressor Proteins genetics
Abstract: Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study., Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant., Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10 -5 ), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10 -8 ) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants., Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
Published: 2016
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6. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

Author: Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, Lawrenson K, Lindstrom S, Ramus SJ, Thompson DJ, Kibel AS, Dansonka-Mieszkowska A, Michael A, Dieffenbach AK, Gentry-Maharaj A, Whittemore AS, Wolk A, Monteiro A, Peixoto A, Kierzek A, Cox A, Rudolph A, Gonzalez-Neira A, Wu AH, Lindblom A, Swerdlow A, Ziogas A, Ekici AB, Burwinkel B, Karlan BY, Nordestgaard BG, Blomqvist C, Phelan C, McLean C, Pearce CL, Vachon C, Cybulski C, Slavov C, Stegmaier C, Maier C, Ambrosone CB, Høgdall CK, Teerlink CC, Kang D, Tessier DC, Schaid DJ, Stram DO, Cramer DW, Neal DE, Eccles D, Flesch-Janys D, Edwards DR, Wokozorczyk D, Levine DA, Yannoukakos D, Sawyer EJ, Bandera EV, Poole EM, Goode EL, Khusnutdinova E, Høgdall E, Song F, Bruinsma F, Heitz F, Modugno F, Hamdy FC, Wiklund F, Giles GG, Olsson H, Wildiers H, Ulmer HU, Pandha H, Risch HA, Darabi H, Salvesen HB, Nevanlinna H, Gronberg H, Brenner H, Brauch H, Anton-Culver H, Song H, Lim HY, McNeish I, Campbell I, Vergote I, Gronwald J, Lubiński J, Stanford JL, Benítez J, Doherty JA, Permuth JB, Chang-Claude J, Donovan JL, Dennis J, Schildkraut JM, Schleutker J, Hopper JL, Kupryjanczyk J, Park JY, Figueroa J, Clements JA, Knight JA, Peto J, Cunningham JM, Pow-Sang J, Batra J, Czene K, Lu KH, Herkommer K, Khaw KT, Matsuo K, Muir K, Offitt K, Chen K, Moysich KB, Aittomäki K, Odunsi K, Kiemeney LA, Massuger LF, Fitzgerald LM, Cook LS, Cannon-Albright L, Hooning MJ, Pike MC, Bolla MK, Luedeke M, Teixeira MR, Goodman MT, Schmidt MK, Riggan M, Aly M, Rossing MA, Beckmann MW, Moisse M, Sanderson M, Southey MC, Jones M, Lush M, Hildebrandt MA, Hou MF, Schoemaker MJ, Garcia-Closas M, Bogdanova N, Rahman N, Le ND, Orr N, Wentzensen N, Pashayan N, Peterlongo P, Guénel P, Brennan P, Paulo P, Webb PM, Broberg P, Fasching PA, Devilee P, Wang Q, Cai Q, Li Q, Kaneva R, Butzow R, Kopperud RK, Schmutzler RK, Stephenson RA, MacInnis RJ, Hoover RN, Winqvist R, Ness R, Milne RL, Travis RC, Benlloch S, Olson SH, McDonnell SK, Tworoger SS, Maia S, Berndt S, Lee SC, Teo SH, Thibodeau SN, Bojesen SE, Gapstur SM, Kjær SK, Pejovic T, Tammela TL, Dörk T, Brüning T, Wahlfors T, Key TJ, Edwards TL, Menon U, Hamann U, Mitev V, Kosma VM, Setiawan VW, Kristensen V, Arndt V, Vogel W, Zheng W, Sieh W, Blot WJ, Kluzniak W, Shu XO, Gao YT, Schumacher F, Freedman ML, Berchuck A, Dunning AM, Simard J, Haiman CA, Spurdle A, Sellers TA, Hunter DJ, Henderson BE, Kraft P, Chanock SJ, Couch FJ, Hall P, Gayther SA, Easton DF, Chenevix-Trench G, Eeles R, Pharoah PD, and Lambrechts D
Subjects: Breast Neoplasms metabolism, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Humans, Male, Meta-Analysis as Topic, Organ Specificity genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms metabolism, Quantitative Trait Loci, Signal Transduction, Breast Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
Abstract: Unlabelled: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)
Published: 2016
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7. Prediction of individual genetic risk to prostate cancer using a polygenic score.

Author: Szulkin R, Whitington T, Eklund M, Aly M, Eeles RA, Easton D, Kote-Jarai ZS, Amin Al Olama A, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubiński J, Kluźniak W, Cannon-Albright L, Brenner H, Butterbach K, Stegmaier C, Park JY, Sellers T, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Gronberg H, and Wiklund F
Subjects: Genetic Variation, Humans, Linkage Disequilibrium, Male, Risk Factors, Genetic Markers, Genetic Predisposition to Disease, Prostatic Neoplasms genetics
Abstract: Background: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction., Methods: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls., Results: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk., Conclusions: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction., (© 2015 Wiley Periodicals, Inc.)
Published: 2015
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8. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

Author: Orr N, Dudbridge F, Dryden N, Maguire S, Novo D, Perrakis E, Johnson N, Ghoussaini M, Hopper JL, Southey MC, Apicella C, Stone J, Schmidt MK, Broeks A, Van't Veer LJ, Hogervorst FB, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Gibson L, Aitken Z, Warren H, Sawyer E, Tomlinson I, Kerin MJ, Miller N, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Guénel P, Truong T, Cordina-Duverger E, Sanchez M, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Benitez J, Zamora MP, Arias Perez JI, Menéndez P, Anton-Culver H, Neuhausen SL, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Hamann U, Brauch H, Justenhoven C, Brüning T, Ko YD, Nevanlinna H, Aittomäki K, Blomqvist C, Khan S, Bogdanova N, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Chenevix-Trench G, Beesley J, Lambrechts D, Moisse M, Floris G, Beuselinck B, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Radice P, Peterlongo P, Peissel B, Pensotti V, Couch FJ, Olson JE, Slettedahl S, Vachon C, Giles GG, Milne RL, McLean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Kristensen V, Alnæs GG, Nord S, Borresen-Dale AL, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar RA, Seynaeve CM, Van Asperen CJ, Garcia-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Darabi H, Eriksson M, Klevebring D, Hooning MJ, Hollestelle A, van Deurzen CH, Kriege M, Hall P, Li J, Liu J, Humphreys K, Cox A, Cross SS, Reed MW, Pharoah PD, Dunning AM, Shah M, Perkins BJ, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Ashworth A, Swerdlow A, Jones M, Schoemaker MJ, Meindl A, Schmutzler RK, Olswold C, Slager S, Toland AE, Yannoukakos D, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Matsuo K, Ito H, Iwata H, Ishiguro J, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Teo SH, Yip CH, Kang P, Ikram MK, Shu XO, Lu W, Gao YT, Cai H, Kang D, Choi JY, Park SK, Noh DY, Hartman M, Miao H, Lim WY, Lee SC, Sangrajrang S, Gaborieau V, Brennan P, Mckay J, Wu PE, Hou MF, Yu JC, Shen CY, Blot W, Cai Q, Signorello LB, Luccarini C, Bayes C, Ahmed S, Maranian M, Healey CS, González-Neira A, Pita G, Alonso MR, Álvarez N, Herrero D, Tessier DC, Vincent D, Bacot F, Hunter DJ, Lindstrom S, Dennis J, Michailidou K, Bolla MK, Easton DF, dos Santos Silva I, Fletcher O, and Peto J
Subjects: Adult, Aged, Asian People genetics, Chromosome Mapping, Enhancer Elements, Genetic, Estrogen Receptor alpha genetics, Female, GATA3 Transcription Factor genetics, Genetic Association Studies, Hepatocyte Nuclear Factor 3-alpha genetics, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Middle Aged, Risk, White People genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 9, Genetic Loci, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis., (© The Author 2015. Published by Oxford University Press.)
Published: 2015
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9. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Author: Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, Maranian MJ, Bolla MK, Wang Q, Shah M, Perkins BJ, Czene K, Eriksson M, Darabi H, Brand JS, Bojesen SE, Nordestgaard BG, Flyger H, Nielsen SF, Rahman N, Turnbull C, Fletcher O, Peto J, Gibson L, dos-Santos-Silva I, Chang-Claude J, Flesch-Janys D, Rudolph A, Eilber U, Behrens S, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Khan S, Aaltonen K, Ahsan H, Kibriya MG, Whittemore AS, John EM, Malone KE, Gammon MD, Santella RM, Ursin G, Makalic E, Schmidt DF, Casey G, Hunter DJ, Gapstur SM, Gaudet MM, Diver WR, Haiman CA, Schumacher F, Henderson BE, Le Marchand L, Berg CD, Chanock SJ, Figueroa J, Hoover RN, Lambrechts D, Neven P, Wildiers H, van Limbergen E, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Couch FJ, Olson JE, Hallberg E, Vachon C, Waisfisz Q, Meijers-Heijboer H, Adank MA, van der Luijt RB, Li J, Liu J, Humphreys K, Kang D, Choi JY, Park SK, Yoo KY, Matsuo K, Ito H, Iwata H, Tajima K, Guénel P, Truong T, Mulot C, Sanchez M, Burwinkel B, Marme F, Surowy H, Sohn C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, González-Neira A, Benitez J, Zamora MP, Perez JI, Shu XO, Lu W, Gao YT, Cai H, Cox A, Cross SS, Reed MW, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Lindblom A, Margolin S, Teo SH, Yip CH, Taib NA, Tan GH, Hooning MJ, Hollestelle A, Martens JW, Collée JM, Blot W, Signorello LB, Cai Q, Hopper JL, Southey MC, Tsimiklis H, Apicella C, Shen CY, Hsiung CN, Wu PE, Hou MF, Kristensen VN, Nord S, Alnaes GI, Giles GG, Milne RL, McLean C, Canzian F, Trichopoulos D, Peeters P, Lund E, Sund M, Khaw KT, Gunter MJ, Palli D, Mortensen LM, Dossus L, Huerta JM, Meindl A, Schmutzler RK, Sutter C, Yang R, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Hartman M, Miao H, Chia KS, Chan CW, Fasching PA, Hein A, Beckmann MW, Haeberle L, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Ashworth A, Orr N, Schoemaker MJ, Swerdlow AJ, Brinton L, Garcia-Closas M, Zheng W, Halverson SL, Shrubsole M, Long J, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Brüning T, Radice P, Peterlongo P, Manoukian S, Bernard L, Bogdanova NV, Dörk T, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Huzarski T, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Kabisch M, Torres D, Neuhausen SL, Anton-Culver H, Luccarini C, Baynes C, Ahmed S, Healey CS, Tessier DC, Vincent D, Bacot F, Pita G, Alonso MR, Álvarez N, Herrero D, Simard J, Pharoah PP, Kraft P, Dunning AM, Chenevix-Trench G, Hall P, and Easton DF
Subjects: Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Microarray Analysis, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
Published: 2015
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10. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.

Author: Rudolph A, Milne RL, Truong T, Knight JA, Seibold P, Flesch-Janys D, Behrens S, Eilber U, Bolla MK, Wang Q, Dennis J, Dunning AM, Shah M, Munday HR, Darabi H, Eriksson M, Brand JS, Olson J, Vachon CM, Hallberg E, Castelao JE, Carracedo A, Torres M, Li J, Humphreys K, Cordina-Duverger E, Menegaux F, Flyger H, Nordestgaard BG, Nielsen SF, Yesilyurt BT, Floris G, Leunen K, Engelhardt EG, Broeks A, Rutgers EJ, Glendon G, Mulligan AM, Cross S, Reed M, Gonzalez-Neira A, Arias Perez JI, Provenzano E, Apicella C, Southey MC, Spurdle A, Häberle L, Beckmann MW, Ekici AB, Dieffenbach AK, Arndt V, Stegmaier C, McLean C, Baglietto L, Chanock SJ, Lissowska J, Sherman ME, Brüning T, Hamann U, Ko YD, Orr N, Schoemaker M, Ashworth A, Kosma VM, Kataja V, Hartikainen JM, Mannermaa A, Swerdlow A, Giles GG, Brenner H, Fasching PA, Chenevix-Trench G, Hopper J, Benítez J, Cox A, Andrulis IL, Lambrechts D, Gago-Dominguez M, Couch F, Czene K, Bojesen SE, Easton DF, Schmidt MK, Guénel P, Hall P, Pharoah PD, Garcia-Closas M, and Chang-Claude J
Subjects: Breast Neoplasms chemistry, Breast Neoplasms etiology, Female, Genetic Loci, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen analysis, Risk Factors, Breast Neoplasms genetics, Gene-Environment Interaction, Genetic Predisposition to Disease
Abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1 × 10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10(-4) ), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10(-5) ), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10(-4) ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies., (© 2014 UICC.)
Published: 2015
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11. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

Author: Kabisch M, Lorenzo Bermejo J, Dünnebier T, Ying S, Michailidou K, Bolla MK, Wang Q, Dennis J, Shah M, Perkins BJ, Czene K, Darabi H, Eriksson M, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Lambrechts D, Neven P, Peeters S, Weltens C, Couch FJ, Olson JE, Wang X, Purrington K, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Peto J, dos-Santos-Silva I, Johnson N, Fletcher O, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Schmidt MK, Broeks A, Cornelissen S, Hogervorst FB, Li J, Brand JS, Humphreys K, Guénel P, Truong T, Menegaux F, Sanchez M, Burwinkel B, Marmé F, Yang R, Bugert P, González-Neira A, Benitez J, Pilar Zamora M, Arias Perez JI, Cox A, Cross SS, Reed MW, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Haiman CA, Schumacher F, Henderson BE, Le Marchand L, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, Kriege M, Koppert LB, Hopper JL, Southey MC, Tsimiklis H, Apicella C, Slettedahl S, Toland AE, Vachon C, Yannoukakos D, Giles GG, Milne RL, McLean C, Fasching PA, Ruebner M, Ekici AB, Beckmann MW, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Ashworth A, Orr N, Schoemaker MJ, Swerdlow A, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Brüning T, Ko YD, Radice P, Peterlongo P, Scuvera G, Fortuzzi S, Bogdanova N, Dörk T, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Zheng W, Shrubsole MJ, Cai Q, Torres D, Anton-Culver H, Kristensen V, Bacot F, Tessier DC, Vincent D, Luccarini C, Baynes C, Ahmed S, Maranian M, Simard J, Chenevix-Trench G, Hall P, Pharoah PD, Dunning AM, Easton DF, and Hamann U
Subjects: 3' Untranslated Regions genetics, Aurora Kinase B genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Case-Control Studies, Cell Cycle Proteins genetics, Female, Genome-Wide Association Study, Humans, Inhibitor of Apoptosis Proteins genetics, Polymorphism, Single Nucleotide, Risk, Survivin, White People genetics, Chromosomal Proteins, Non-Histone genetics, Genetic Predisposition to Disease, Receptors, Estrogen metabolism
Abstract: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2015
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12. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Author: Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Zamora MP, Menéndez-Rodríguez P, Hardisson D, Mendiola M, González-Neira A, Pita G, Alonso MR, Dennis J, Wang Q, Bolla MK, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Ko YD, Brauch H, Hamann U, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Matsuo K, Ito H, Iwata H, Tajima K, Li J, Brand JS, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lambrechts D, Peuteman G, Christiaens MR, Smeets A, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Hartman M, Hui M, Yen Lim W, Wan Chan C, Marme F, Yang R, Bugert P, Lindblom A, Margolin S, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Bojesen SE, Nordestgaard BG, Flyger H, Hooning MJ, Kriege M, van den Ouweland AM, Koppert LB, Fletcher O, Johnson N, dos-Santos-Silva I, Peto J, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Cox A, Cross SS, Reed MW, Schmidt MK, Broeks A, Cornelissen S, Braaf L, Kang D, Choi JY, Park SK, Noh DY, Simard J, Dumont M, Goldberg MS, Labrèche F, Fasching PA, Hein A, Ekici AB, Beckmann MW, Radice P, Peterlongo P, Azzollini J, Barile M, Sawyer E, Tomlinson I, Kerin M, Miller N, Hopper JL, Schmidt DF, Makalic E, Southey MC, Hwang Teo S, Har Yip C, Sivanandan K, Tay WT, Shen CY, Hsiung CN, Yu JC, Hou MF, Guénel P, Truong T, Sanchez M, Mulot C, Blot W, Cai Q, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Bogdanova N, Dörk T, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Shu XO, Lu W, Gao YT, Zhang B, Couch FJ, Toland AE, Yannoukakos D, Sangrajrang S, McKay J, Wang X, Olson JE, Vachon C, Purrington K, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Devilee P, Tollenaar RA, Seynaeve C, Czene K, Eriksson M, Humphreys K, Darabi H, Ahmed S, Shah M, Pharoah PD, Hall P, Giles GG, Benítez J, Dunning AM, Chenevix-Trench G, and Easton DF
Subjects: A Kinase Anchor Proteins genetics, Adult, Alleles, Ataxin-7, Case-Control Studies, Cytoskeletal Proteins genetics, Female, Genome-Wide Association Study, Humans, Middle Aged, NIMA-Related Kinases, Nerve Tissue Proteins genetics, Protein Serine-Threonine Kinases genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act., (© The Author 2014. Published by Oxford University Press.)
Published: 2014
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13. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Author: Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Wokołorczyk D, Kluźniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Cook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, and Haiman CA
Subjects: Genome-Wide Association Study, Genotype, Humans, Male, Risk Assessment, Risk Factors, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Published: 2014
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14. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author: Sawyer E, Roylance R, Petridis C, Brook MN, Nowinski S, Papouli E, Fletcher O, Pinder S, Hanby A, Kohut K, Gorman P, Caneppele M, Peto J, Dos Santos Silva I, Johnson N, Swann R, Dwek M, Perkins KA, Gillett C, Houlston R, Ross G, De Ieso P, Southey MC, Hopper JL, Provenzano E, Apicella C, Wesseling J, Cornelissen S, Keeman R, Fasching PA, Jud SM, Ekici AB, Beckmann MW, Kerin MJ, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Kerbrat P, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Perez JI, Menéndez P, Benitez J, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Lochmann M, Brauch H, Fischer HP, Ko YD, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Bogdanova NV, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Chenevix-Trench G, Lambrechts D, Weltens C, Van Limbergen E, Hatse S, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Volorio S, Giles GG, Severi G, Baglietto L, McLean CA, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Kristensen V, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devillee P, Tollenaar RA, Seynaeve CM, Kriege M, Figueroa J, Chanock SJ, Sherman ME, Hooning MJ, Hollestelle A, van den Ouweland AM, van Deurzen CH, Li J, Czene K, Humphreys K, Cox A, Cross SS, Reed MW, Shah M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Couch FJ, Hallberg E, González-Neira A, Pita G, Alonso MR, Tessier DC, Vincent D, Bacot F, Bolla MK, Wang Q, Dennis J, Michailidou K, Dunning AM, Hall P, Easton D, Pharoah P, Schmidt MK, Tomlinson I, and Garcia-Closas M
Subjects: Case-Control Studies, Female, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide genetics, Breast Neoplasms genetics, Carcinoma in Situ genetics, Carcinoma, Lobular genetics, Genetic Predisposition to Disease genetics
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
Published: 2014
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15. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium.

Author: Milne RL, Herranz J, Michailidou K, Dennis J, Tyrer JP, Zamora MP, Arias-Perez JI, González-Neira A, Pita G, Alonso MR, Wang Q, Bolla MK, Czene K, Eriksson M, Humphreys K, Darabi H, Li J, Anton-Culver H, Neuhausen SL, Ziogas A, Clarke CA, Hopper JL, Dite GS, Apicella C, Southey MC, Chenevix-Trench G, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Bojesen SE, Nordestgaard BG, Flyger H, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Olson JE, Vachon C, Purrington K, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Dunning AM, Shah M, Guénel P, Truong T, Sanchez M, Mulot C, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, Collée JM, Jager A, Cox A, Brock IW, Reed MW, Devilee P, Tollenaar RA, Seynaeve C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Dumont M, Soucy P, Dörk T, Bogdanova NV, Hamann U, Försti A, Rüdiger T, Ulmer HU, Fasching PA, Häberle L, Ekici AB, Beckmann MW, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Radice P, Peterlongo P, Peissel B, Mariani P, Giles GG, Severi G, Baglietto L, Sawyer E, Tomlinson I, Kerin M, Miller N, Marme F, Burwinkel B, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Alnæs GG, Kristensen V, Børresen-Dale AL, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Schmidt MK, Broeks A, Verhoef S, Rutgers EJ, Brauch H, Brüning T, Ko YD, Couch FJ, Toland AE, Yannoukakos D, Pharoah PD, Hall P, Benítez J, Malats N, and Easton DF
Subjects: Case-Control Studies, Epistasis, Genetic genetics, Female, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Genetic Predisposition to Disease
Abstract: Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
Published: 2014
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16. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

Author: Agarwal D, Pineda S, Michailidou K, Herranz J, Pita G, Moreno LT, Alonso MR, Dennis J, Wang Q, Bolla MK, Meyer KB, Menéndez-Rodríguez P, Hardisson D, Mendiola M, González-Neira A, Lindblom A, Margolin S, Swerdlow A, Ashworth A, Orr N, Jones M, Matsuo K, Ito H, Iwata H, Kondo N, Hartman M, Hui M, Lim WY, Iau PT, Sawyer E, Tomlinson I, Kerin M, Miller N, Kang D, Choi J-, Park SK, Noh D-, Hopper JL, Schmidt DF, Makalic E, Southey MC, Teo SH, Yip CH, Sivanandan K, Tay W-, Brauch H, Brüning T, Hamann U, Dunning AM, Shah M, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Schmidt MK, Broeks A, Rosenberg EH, van't Veer LJ, Fasching PA, Renner SP, Ekici AB, Beckmann MW, Shen C-, Hsiung C-, Yu J-, Hou M-, Blot W, Cai Q, Wu AH, Tseng C-, Van Den Berg D, Stram DO, Cox A, Brock IW, Reed MW, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Shu X-, Lu W, Gao Y-, Zhang B, Radice P, Peterlongo P, Manoukian S, Mariette F, Sangrajrang S, McKay J, Couch FJ, Toland AE, Yannoukakos D, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Marme F, Burwinkel B, Guénel P, Truong T, Sanchez M, Mulot C, Bojesen SE, Nordestgaard BG, Flyer H, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Mannermaa A, Kataja V, Kosma V-, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Olson JE, Vachon C, Purrington K, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Marchand LL, Simard J, Dumont M, Goldberg MS, Labréche F, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Devilee P, Tollenaar RA, Seynaeve C, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Czene K, Eriksson M, Humphreys K, Darabi H, Hooning MJ, Kriege M, Collée JM, Tilanus-Linthorst M, Li J, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Bogdanova N, Dörk T, Hall P, Chenevix-Trench G, Easton DF, Pharroah PD, Arias-Perez JI, Zamora P, Benítez J, and Milne RL
Subjects: Case-Control Studies, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide genetics, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics, Receptor, Fibroblast Growth Factor, Type 4 genetics, Receptor, Fibroblast Growth Factor, Type 5 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2 genetics
Abstract: Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium., Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression., Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2., Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
Published: 2014
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17. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions.

Author: Schoeps A, Rudolph A, Seibold P, Dunning AM, Milne RL, Bojesen SE, Swerdlow A, Andrulis I, Brenner H, Behrens S, Orr N, Jones M, Ashworth A, Li J, Cramp H, Connley D, Czene K, Darabi H, Chanock SJ, Lissowska J, Figueroa JD, Knight J, Glendon G, Mulligan AM, Dumont M, Severi G, Baglietto L, Olson J, Vachon C, Purrington K, Moisse M, Neven P, Wildiers H, Spurdle A, Kosma VM, Kataja V, Hartikainen JM, Hamann U, Ko YD, Dieffenbach AK, Arndt V, Stegmaier C, Malats N, Arias Perez JI, Benítez J, Flyger H, Nordestgaard BG, Truong T, Cordina-Duverger E, Menegaux F, dos Santos Silva I, Fletcher O, Johnson N, Häberle L, Beckmann MW, Ekici AB, Braaf L, Atsma F, van den Broek AJ, Makalic E, Schmidt DF, Southey MC, Cox A, Simard J, Giles GG, Lambrechts D, Mannermaa A, Brauch H, Guénel P, Peto J, Fasching PA, Hopper J, Flesch-Janys D, Couch F, Chenevix-Trench G, Pharoah PD, Garcia-Closas M, Schmidt MK, Hall P, Easton DF, and Chang-Claude J
Subjects: Adolescent, Body Height, Body Mass Index, Chromosomes, Human, Pair 21 genetics, Chromosomes, Human, Pair 6 genetics, Female, Genetic Loci genetics, Humans, Linkage Disequilibrium genetics, Menarche, Middle Aged, Parity, Postmenopause, White People genetics, Breast Neoplasms genetics, Gene-Environment Interaction, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics
Abstract: Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10(-05)). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci., (© 2013 WILEY PERIODICALS, INC.)
Published: 2014
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18. Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

Author: Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK, Chang-Claude J, Bojesen SE, Bolla MK, Wang Q, Dicks E, Lee A, Turnbull C, Rahman N, Fletcher O, Peto J, Gibson L, Dos Santos Silva I, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Czene K, Irwanto A, Liu J, Waisfisz Q, Meijers-Heijboer H, Adank M, van der Luijt RB, Hein R, Dahmen N, Beckman L, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Hopper JL, Southey MC, Makalic E, Schmidt DF, Uitterlinden AG, Hofman A, Hunter DJ, Chanock SJ, Vincent D, Bacot F, Tessier DC, Canisius S, Wessels LF, Haiman CA, Shah M, Luben R, Brown J, Luccarini C, Schoof N, Humphreys K, Li J, Nordestgaard BG, Nielsen SF, Flyger H, Couch FJ, Wang X, Vachon C, Stevens KN, Lambrechts D, Moisse M, Paridaens R, Christiaens MR, Rudolph A, Nickels S, Flesch-Janys D, Johnson N, Aitken Z, Aaltonen K, Heikkinen T, Broeks A, Veer LJ, van der Schoot CE, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Zamora MP, Perez JI, Pita G, Alonso MR, Cox A, Brock IW, Cross SS, Reed MW, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Henderson BE, Schumacher F, Le Marchand L, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, van den Ouweland AM, Jager A, Bui QM, Stone J, Dite GS, Apicella C, Tsimiklis H, Giles GG, Severi G, Baglietto L, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Müller H, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Jones M, Figueroa J, Lissowska J, Brinton L, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Brüning T, Radice P, Peterlongo P, Manoukian S, Bonanni B, Devilee P, Tollenaar RA, Seynaeve C, van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Durda K, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Bogdanova NV, Antonenkova NN, Dörk T, Kristensen VN, Anton-Culver H, Slager S, Toland AE, Edge S, Fostira F, Kang D, Yoo KY, Noh DY, Matsuo K, Ito H, Iwata H, Sueta A, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Shu XO, Lu W, Gao YT, Cai H, Teo SH, Yip CH, Phuah SY, Cornes BK, Hartman M, Miao H, Lim WY, Sng JH, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Shen CY, Hsiung CN, Wu PE, Ding SL, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Blot WJ, Signorello LB, Cai Q, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Simard J, Garcia-Closas M, Pharoah PD, Chenevix-Trench G, Dunning AM, Benitez J, and Easton DF
Subjects: Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Risk Factors, Breast Neoplasms etiology, Genetic Loci genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics
Abstract: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Published: 2013
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19. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

Author: Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, Orr N, Rhie SK, Riboli E, Feigelson HS, Le Marchand L, Buring JE, Eccles D, Miron P, Fasching PA, Brauch H, Chang-Claude J, Carpenter J, Godwin AK, Nevanlinna H, Giles GG, Cox A, Hopper JL, Bolla MK, Wang Q, Dennis J, Dicks E, Howat WJ, Schoof N, Bojesen SE, Lambrechts D, Broeks A, Andrulis IL, Guénel P, Burwinkel B, Sawyer EJ, Hollestelle A, Fletcher O, Winqvist R, Brenner H, Mannermaa A, Hamann U, Meindl A, Lindblom A, Zheng W, Devillee P, Goldberg MS, Lubinski J, Kristensen V, Swerdlow A, Anton-Culver H, Dörk T, Muir K, Matsuo K, Wu AH, Radice P, Teo SH, Shu XO, Blot W, Kang D, Hartman M, Sangrajrang S, Shen CY, Southey MC, Park DJ, Hammet F, Stone J, Veer LJ, Rutgers EJ, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Peto J, Schrauder MG, Ekici AB, Beckmann MW, Dos Santos Silva I, Johnson N, Warren H, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Truong T, Laurent-Puig P, Kerbrat P, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Perez JI, Menéndez P, Müller H, Arndt V, Stegmaier C, Lichtner P, Lochmann M, Justenhoven C, Ko YD, Muranen TA, Aittomäki K, Blomqvist C, Greco D, Heikkinen T, Ito H, Iwata H, Yatabe Y, Antonenkova NN, Margolin S, Kataja V, Kosma VM, Hartikainen JM, Balleine R, Tseng CC, Berg DV, Stram DO, Neven P, Dieudonné AS, Leunen K, Rudolph A, Nickels S, Flesch-Janys D, Peterlongo P, Peissel B, Bernard L, Olson JE, Wang X, Stevens K, Severi G, Baglietto L, McLean C, Coetzee GA, Feng Y, Henderson BE, Schumacher F, Bogdanova NV, Labrèche F, Dumont M, Yip CH, Taib NA, Cheng CY, Shrubsole M, Long J, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Knight JA, Glendon G, Mulligan AM, Tollenaar RA, Seynaeve CM, Kriege M, Hooning MJ, van den Ouweland AM, van Deurzen CH, Lu W, Gao YT, Cai H, Balasubramanian SP, Cross SS, Reed MW, Signorello L, Cai Q, Shah M, Miao H, Chan CW, Chia KS, Jakubowska A, Jaworska K, Durda K, Hsiung CN, Wu PE, Yu JC, Ashworth A, Jones M, Tessier DC, González-Neira A, Pita G, Alonso MR, Vincent D, Bacot F, Ambrosone CB, Bandera EV, John EM, Chen GK, Hu JJ, Rodriguez-Gil JL, Bernstein L, Press MF, Ziegler RG, Millikan RM, Deming-Halverson SL, Nyante S, Ingles SA, Waisfisz Q, Tsimiklis H, Makalic E, Schmidt D, Bui M, Gibson L, Müller-Myhsok B, Schmutzler RK, Hein R, Dahmen N, Beckmann L, Aaltonen K, Czene K, Irwanto A, Liu J, Turnbull C, Rahman N, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Olswold C, Slager S, Pilarski R, Ademuyiwa F, Konstantopoulou I, Martin NG, Montgomery GW, Slamon DJ, Rauh C, Lux MP, Jud SM, Bruning T, Weaver J, Sharma P, Pathak H, Tapper W, Gerty S, Durcan L, Trichopoulos D, Tumino R, Peeters PH, Kaaks R, Campa D, Canzian F, Weiderpass E, Johansson M, Khaw KT, Travis R, Clavel-Chapelon F, Kolonel LN, Chen C, Beck A, Hankinson SE, Berg CD, Hoover RN, Lissowska J, Figueroa JD, Chasman DI, Gaudet MM, Diver WR, Willett WC, Hunter DJ, Simard J, Benitez J, Dunning AM, Sherman ME, Chenevix-Trench G, Chanock SJ, Hall P, Pharoah PD, Vachon C, Easton DF, Haiman CA, and Kraft P
Subjects: Breast Neoplasms metabolism, Breast Neoplasms pathology, Case-Control Studies, Cooperative Behavior, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Oligonucleotide Array Sequence Analysis, Receptors, Estrogen genetics, Risk Factors, Breast Neoplasms etiology, Genetic Loci genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Receptors, Estrogen metabolism
Abstract: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
Published: 2013
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20. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus.

Author: Stevens KN, Fredericksen Z, Vachon CM, Wang X, Margolin S, Lindblom A, Nevanlinna H, Greco D, Aittomäki K, Blomqvist C, Chang-Claude J, Vrieling A, Flesch-Janys D, Sinn HP, Wang-Gohrke S, Nickels S, Brauch H, Ko YD, Fischer HP, Schmutzler RK, Meindl A, Bartram CR, Schott S, Engel C, Godwin AK, Weaver J, Pathak HB, Sharma P, Brenner H, Müller H, Arndt V, Stegmaier C, Miron P, Yannoukakos D, Stavropoulou A, Fountzilas G, Gogas HJ, Swann R, Dwek M, Perkins A, Milne RL, Benítez J, Zamora MP, Pérez JI, Bojesen SE, Nielsen SF, Nordestgaard BG, Flyger H, Guénel P, Truong T, Menegaux F, Cordina-Duverger E, Burwinkel B, Marmé F, Schneeweiss A, Sohn C, Sawyer E, Tomlinson I, Kerin MJ, Peto J, Johnson N, Fletcher O, Dos Santos Silva I, Fasching PA, Beckmann MW, Hartmann A, Ekici AB, Lophatananon A, Muir K, Puttawibul P, Wiangnon S, Schmidt MK, Broeks A, Braaf LM, Rosenberg EH, Hopper JL, Apicella C, Park DJ, Southey MC, Swerdlow AJ, Ashworth A, Orr N, Schoemaker MJ, Anton-Culver H, Ziogas A, Bernstein L, Dur CC, Shen CY, Yu JC, Hsu HM, Hsiung CN, Hamann U, Dünnebier T, Rüdiger T, Ulmer HU, Pharoah PP, Dunning AM, Humphreys MK, Wang Q, Cox A, Cross SS, Reed MW, Hall P, Czene K, Ambrosone CB, Ademuyiwa F, Hwang H, Eccles DM, Garcia-Closas M, Figueroa JD, Sherman ME, Lissowska J, Devilee P, Seynaeve C, Tollenaar RA, Hooning MJ, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, John EM, Miron A, Alnæs GG, Kristensen V, Børresen-Dale AL, Giles GG, Baglietto L, McLean CA, Severi G, Kosel ML, Pankratz VS, Slager S, Olson JE, Radice P, Peterlongo P, Manoukian S, Barile M, Lambrechts D, Hatse S, Dieudonne AS, Christiaens MR, Chenevix-Trench G, Beesley J, Chen X, Mannermaa A, Kosma VM, Hartikainen JM, Soini Y, Easton DF, and Couch FJ
Subjects: Breast Neoplasms chemistry, Chromosome Mapping, Female, Genetic Loci, Humans, Receptors, Progesterone analysis, Risk, Breast Neoplasms genetics, Chromosomes, Human, Pair 19, Genetic Predisposition to Disease, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis
Abstract: The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways., (©2012 AACR.)
Published: 2012
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21. Genome-wide association analysis identifies three new breast cancer susceptibility loci.

Author: Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, Dennis J, Wang Q, Humphreys MK, Luccarini C, Baynes C, Conroy D, Maranian M, Ahmed S, Driver K, Johnson N, Orr N, dos Santos Silva I, Waisfisz Q, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Hall P, Czene K, Irwanto A, Liu J, Nevanlinna H, Aittomäki K, Blomqvist C, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Chang-Claude J, Hein R, Nickels S, Flesch-Janys D, Tsimiklis H, Makalic E, Schmidt D, Bui M, Hopper JL, Apicella C, Park DJ, Southey M, Hunter DJ, Chanock SJ, Broeks A, Verhoef S, Hogervorst FB, Fasching PA, Lux MP, Beckmann MW, Ekici AB, Sawyer E, Tomlinson I, Kerin M, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Cordina-Duverger E, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Alonso MR, González-Neira A, Benítez J, Anton-Culver H, Ziogas A, Bernstein L, Dur CC, Brenner H, Müller H, Arndt V, Stegmaier C, Justenhoven C, Brauch H, Brüning T, Wang-Gohrke S, Eilber U, Dörk T, Schürmann P, Bremer M, Hillemanns P, Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Bermisheva M, Prokofieva D, Khusnutdinova E, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Manoukian S, Bonanni B, Fortuzzi S, Peterlongo P, Couch FJ, Wang X, Stevens K, Lee A, Giles GG, Baglietto L, Severi G, McLean C, Alnaes GG, Kristensen V, Børrensen-Dale AL, John EM, Miron A, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Glendon G, Mulligan AM, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Figueroa JD, Garcia-Closas M, Brinton L, Lissowska J, Hooning MJ, Hollestelle A, Oldenburg RA, van den Ouweland AM, Cox A, Reed MW, Shah M, Jakubowska A, Lubinski J, Jaworska K, Durda K, Jones M, Schoemaker M, Ashworth A, Swerdlow A, Beesley J, Chen X, Muir KR, Lophatananon A, Rattanamongkongul S, Chaiwerawattana A, Kang D, Yoo KY, Noh DY, Shen CY, Yu JC, Wu PE, Hsiung CN, Perkins A, Swann R, Velentzis L, Eccles DM, Tapper WJ, Gerty SM, Graham NJ, Ponder BA, Chenevix-Trench G, Pharoah PD, Lathrop M, Dunning AM, Rahman N, Peto J, and Easton DF
Subjects: Female, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide genetics, Principal Component Analysis, White People genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 12 genetics, Chromosomes, Human, Pair 21 genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics
Abstract: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Published: 2012
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22. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author: Hein R, Maranian M, Hopper JL, Kapuscinski MK, Southey MC, Park DJ, Schmidt MK, Broeks A, Hogervorst FB, Bueno-de-Mesquita HB, Muir KR, Lophatananon A, Rattanamongkongul S, Puttawibul P, Fasching PA, Hein A, Ekici AB, Beckmann MW, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Sawyer E, Tomlinson I, Kerin M, Miller N, Marmee F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Cordina-Duverger E, Menegaux F, Truong T, Bojesen SE, Nordestgaard BG, Flyger H, Milne RL, Perez JI, Zamora MP, Benítez J, Anton-Culver H, Ziogas A, Bernstein L, Clarke CA, Brenner H, Müller H, Arndt V, Stegmaier C, Rahman N, Seal S, Turnbull C, Renwick A, Meindl A, Schott S, Bartram CR, Schmutzler RK, Brauch H, Hamann U, Ko YD, Wang-Gohrke S, Dörk T, Schürmann P, Karstens JH, Hillemanns P, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Bogdanova NV, Zalutsky IV, Antonenkova NN, Bermisheva M, Prokovieva D, Farahtdinova A, Khusnutdinova E, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen J, Chen X, Beesley J, Lambrechts D, Zhao H, Neven P, Wildiers H, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Manoukian S, Barile M, Couch FJ, Olson JE, Wang X, Fredericksen Z, Giles GG, Baglietto L, McLean CA, Severi G, Offit K, Robson M, Gaudet MM, Vijai J, Alnæs GG, Kristensen V, Børresen-Dale AL, John EM, Miron A, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Figueroa JD, García-Closas M, Lissowska J, Sherman ME, Hooning M, Martens JW, Seynaeve C, Collée M, Hall P, Humpreys K, Czene K, Liu J, Cox A, Brock IW, Cross SS, Reed MW, Ahmed S, Ghoussaini M, Pharoah PD, Kang D, Yoo KY, Noh DY, Jakubowska A, Jaworska K, Durda K, Złowocka E, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Shen CY, Yu JC, Hsu HM, Hou MF, Orr N, Schoemaker M, Ashworth A, Swerdlow A, Trentham-Dietz A, Newcomb PA, Titus L, Egan KM, Chenevix-Trench G, Antoniou AC, Humphreys MK, Morrison J, Chang-Claude J, Easton DF, and Dunning AM
Subjects: Asia, Europe, Female, Haplotypes genetics, Humans, Linkage Disequilibrium genetics, Receptors, Estrogen genetics, Risk Factors, Breast Neoplasms genetics, Chromosomes, Human, Pair 6 genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
Published: 2012
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23. Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

Author: Milne RL, Goode EL, García-Closas M, Couch FJ, Severi G, Hein R, Fredericksen Z, Malats N, Zamora MP, Arias Pérez JI, Benítez J, Dörk T, Schürmann P, Karstens JH, Hillemanns P, Cox A, Brock IW, Elliot G, Cross SS, Seal S, Turnbull C, Renwick A, Rahman N, Shen CY, Yu JC, Huang CS, Hou MF, Nordestgaard BG, Bojesen SE, Lanng C, Grenaker Alnæs G, Kristensen V, Børrensen-Dale AL, Hopper JL, Dite GS, Apicella C, Southey MC, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Chang-Claude J, Wang-Gohrke S, Radice P, Peterlongo P, Manoukian S, Barile M, Giles GG, Baglietto L, John EM, Miron A, Chanock SJ, Lissowska J, Sherman ME, Figueroa JD, Bogdanova NV, Antonenkova NN, Zalutsky IV, Rogov YI, Fasching PA, Bayer CM, Ekici AB, Beckmann MW, Brenner H, Müller H, Arndt V, Stegmaier C, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Meindl A, Heil J, Bartram CR, Schmutzler RK, Thomas GD, Hoover RN, Fletcher O, Gibson LJ, dos Santos Silva I, Peto J, Nickels S, Flesch-Janys D, Anton-Culver H, Ziogas A, Sawyer E, Tomlinson I, Kerin M, Miller N, Schmidt MK, Broeks A, Van 't Veer LJ, Tollenaar RA, Pharoah PD, Dunning AM, Pooley KA, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Jakubowska A, Lubinski J, Jaworska K, Durda K, Kang D, Yoo KY, Noh DY, Ahn SH, Hunter DJ, Hankinson SE, Kraft P, Lindstrom S, Chen X, Beesley J, Hamann U, Harth V, Justenhoven C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Hooning M, Hollestelle A, Oldenburg RA, Tilanus-Linthorst M, Khusnutdinova E, Bermisheva M, Prokofieva D, Farahtdinova A, Olson JE, Wang X, Humphreys MK, Wang Q, Chenevix-Trench G, and Easton DF
Subjects: Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Intraductal, Noninfiltrating pathology, Case-Control Studies, Cohort Studies, Female, Follow-Up Studies, Humans, Neoplasm Grading, Polymorphism, Single Nucleotide, Prognosis, Receptors, Estrogen genetics, Risk Factors, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Carcinoma, Intraductal, Noninfiltrating genetics, Chromosomes, Human, Pair 5 genetics, Genetic Predisposition to Disease, Receptors, Progesterone genetics
Abstract: Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium., Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression., Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 × 10(-18) vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; P(trend) = 5 × 10(-7)]., Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer., Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants., (©2011 AACR)
Published: 2011
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24. Testicular, other genital, and breast cancers in first-degree relatives of testicular cancer patients and controls.

Author: Bromen K, Stang A, Baumgardt-Elms C, Stegmaier C, Ahrens W, Metz KA, and Jöckel KH
Subjects: Adolescent, Adult, Age Distribution, Aged, Breast Neoplasms, Male epidemiology, Case-Control Studies, Cohort Studies, Confidence Intervals, Family, Genital Neoplasms, Male epidemiology, Germany epidemiology, Humans, Incidence, Male, Middle Aged, Odds Ratio, Pedigree, Prognosis, Risk Assessment, Seminoma epidemiology, Testicular Neoplasms epidemiology, Breast Neoplasms, Male genetics, Genetic Predisposition to Disease, Genital Neoplasms, Male genetics, Seminoma genetics, Testicular Neoplasms genetics
Abstract: Previous studies showed an increased prevalence of testicular cancer among fathers and brothers of testicular cancer patients. We examined whether testicular, other genital, and breast cancers aggregate in parents and siblings of testicular cancer patients in a population-based case-control study, including males, ages 15 to 69 years at diagnosis, with primary malignant tumors of the testes or extragonadal germ cell tumors. Controls were ascertained through the mandatory registries of residents and frequency matched to the cases by age and region of residence. In a face-to-face interview, 269 cases and 797 controls provided health-related information on parents and siblings. We calculated odds ratios (OR) and corresponding 95% confidence intervals (95% CI) based on the generalized estimating equations technique, adjusting for the matching variables and relatives' age. Three (1.1%) fathers and eight (3.2%) brothers of cases were affected with testicular cancer compared with four (0.5%) fathers and two (0.2%) brothers of controls. The OR (95% CI) of familial testicular cancer was 6.6 (2.35-18.77). Only nonseminoma patients had fathers with testicular cancer, whereas the affected brothers were all related to seminoma patients. Overall, we found an increased risk for genital other than testicular cancers (OR 2.5, 95% CI 1.43-4.43). For breast cancer, we detected an increased risk in sisters (OR 9.5, 95% CI 2.01-45.16, adjusted for age of study participant and age of sister) but not in mothers. Our findings support the hypothesis that testicular and other genital cancers have a common familial component that may be due to genetic and shared exogenous factors such as estrogen exposure during fetal development.
Published: 2004

25. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

Author: Lin, W.Y., Camp, N.J., Ghoussaini, M., Beesley, J., Michailidou, K., Hopper, J.L., Apicella, C., Southey, M.C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Rutgers, E.J.T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M.K., Wang, Q., Dennis, J., Sawyer, E.J., Cheng, T., Tomlinson, I., Kerin, M.J., Miller, N., Marme, F., Surowy, H.M., Burwinkel, B., Guenel, P., Truong, T., Menegaux, F., Mulot, C., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrera, D., Anton-Culver, H., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Meindl, A., Lichtner, P., Schmutzler, R.K., Muller-Myhsok, B., Brauch, H., Bruning, T., Ko, Y.D., Tessier, D.C., Vincent, D., Bacot, F., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Matsuo, K., Ito, H., Iwata, H., Horio, A., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Neven, P., Wauters, E., Wildiers, H., Lambrechts, D., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Bonanni, B., Couch, F.J., Wang, X.S., Vachon, C., Purrington, K., Giles, G.G., Milne, R.L., Mclean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Teo, S.H., Yip, C.H., Hassan, N., Vithana, E.N., Kristensen, V., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Lissowska, J., Brinton, L., Czene, K., Darabi, H., Eriksson, M., Brand, J.S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Li, J.M., Liu, J.J., Humphreys, K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Cross, S.S., Reed, M.W.R., Blot, W., Signorello, L.B., Cai, Q.Y., Pharoah, P.D.P., Perkins, B., Shah, M., Blows, F.M., Kang, D., Yoo, K.Y., Noh, D.Y., Hartman, M., Miao, H., Chia, K.S., Putti, T.C., Hamann, U., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Slager, S., Toland, A.E., Yannoukakos, D., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Ashworth, A., Jones, M., Orr, N., Swerdlow, A.J., Tsimiklis, H., Makalic, E., Schmidt, D.F., Bui, Q.M., Chanock, S.J., Hunter, D.J., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Muranen, T.A., Heikkinen, T., Irwanto, A., Rahman, N., Turnbull, C.A., Waisfisz, Q., Meijers-Heijboer, H.E.J., Adank, M.A., Luijt, R.B. van der, Hall, P., Chenevix-Trench, G., Dunning, A., Easton, D.F., Cox, A., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Breast Ovarian Canc Susceptibility, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Human Genetics, Human genetics, CCA - Oncogenesis, Ghoussaini, Maya [0000-0002-2415-2143], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Genotyping Techniques, Research Support, U.S. Gov't, P.H.S, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-wide association study, P.H.S, Medical and Health Sciences, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Medizinische Fakultät, Genetics(clinical), Non-U.S. Gov't, Genetics (clinical), Genetics, Genetics & Heredity, variants, Caspase 8, Research Support, Non-U.S. Gov't, Association Studies Articles, General Medicine, Biological Sciences, ddc, Chromosomes, Human, Pair 2, kConFab Investigators, Female, GENICA Network, Australian Ovarian Cancer Study Group, European Continental Ancestry Group, Non-P.H.S, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Research Support, Polymorphism, Single Nucleotide, White People, N.I.H, Breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, medicine, Journal Article, Humans, Genetic Predisposition to Disease, ddc:610, gene, Genotyping, Molecular Biology, Genetic association, disease, Extramural, Proteins, Odds ratio, medicine.disease, susceptibility loci, Minor allele frequency, Case-Control Studies, genome-wide association, enhancers, U.S. Gov't, casp8, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10-5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P=3 × 10-6), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10-9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8might be the target gene, suggesting amechanism involving apoptosis.
Published: 2016

26. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author: Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, H-Y, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, HS, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindstrom, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA, Pasaniuc, B, Cook, M, Guy, M, Govindasami, K, Leongamornlert, D, Sawyer, EJ, Wilkinson, R, Saunders, EJ, Tymrakiewicz, M, Dadaev, T, Morgan, A, Fischer, C, Hazel, S, Livni, N, Lophatananon, A, Pedersen, J, Hopper, JL, Adolfson, J, Stattin, P, Johansson, J-E, Cavalli-Bjoerkman, C, Karlsson, A, Broms, M, Auvinen, A, Kujala, P, Maeaettaenen, L, Murtola, T, Taari, K, Weischer, M, Nielsen, SF, Klarskov, P, Roder, A, Iversen, P, Wallinder, H, Tillmans, L, Riska, S, Wang, L, Rinckleb, A, Lubiski, J, Stegmaier, C, Pow-Sang, J, Park, H, Radlein, S, Rincon, M, Haley, J, Zachariah, B, Kachakova, D, Popov, E, Mitkova, A, Vlahova, A, Dikov, T, Christova, S, Heathcote, P, Wood, G, Malone, G, Saunders, K, Eckert, A, Yeadon, T, Kerr, K, Collins, A, Turner, M, Srinivasan, S, Kedda, M-A, Alexander, K, Omara, T, Wu, H, Henrique, R, Pinto, P, Santos, J, Barros-Silva, J, Pharoah, Paul [0000-0001-8494-732X], Trynka, Gosia [0000-0002-6955-9529], Apollo - University of Cambridge Repository, Clinicum, Department of Surgery, Urologian yksikkö, and University of Helsinki
Subjects: 0301 basic medicine, Male, Genetics and Molecular Biology (all), Linkage disequilibrium, Inheritance Patterns, COMMON DISEASES, General Physics and Astronomy, Genome-wide association study, urologic and male genital diseases, Biochemistry, Linkage Disequilibrium, Epigenesis, Genetic, Histones, Prostate cancer, Genotype, ELEMENTS, genetics, SNPS, ENCODE, RISK, PITFALLS, Genetics, African Americans, Multidisciplinary, Tumor, biological sciences, Chemistry (all), Acetylation, Single Nucleotide, 3. Good health, Centre for Surgical Research, SUSCEPTIBILITY LOCI, Science, 3122 Cancers, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, PRACTICAL consortium, General Biochemistry, Genetics and Molecular Biology, White People, Article, Cell Line, RC0254, 03 medical and health sciences, Physics and Astronomy (all), Atlases as Topic, Genetic, Cell Line, Tumor, MD Multidisciplinary, medicine, SNP, Humans, cancer, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Polymorphism, Genetic association, Cancer och onkologi, COMPLEX TRAITS, Prostatic Neoplasms, General Chemistry, Heritability, ta3122, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Black or African American, ENHANCERS, 030104 developmental biology, Genetic Loci, Genome-Wide Association Study, Biochemistry, Genetics and Molecular Biology (all), Cancer and Oncology, 3111 Biomedicine, Epigenesis
Abstract: Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa., Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.
Published: 2016

27. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

Author: Mavaddat, N., Pharoah, P.D.P., Michailidou, K., Tyrer, J., Brook, M.N., Bolla, M.K., Wang, Q., Dennis, J., Dunning, A.M., Shah, M., Luben, R., Brown, J., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Czene, K., Darabi, H., Eriksson, M., Peto, J., dos-Santos-Silva, I., Dudbridge, F., Johnson, N., Schmidt, M.K., Broeks, A., Verhoef, S., Rutgers, E.J., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M.J., Figueroa, J., Chanock, S.J., Brinton, L., Lissowska, J., Couch, F.J., Olson, J.E., Vachon, C., Pankratz, V.S., Lambrechts, D., Wildiers, H., Ongeval, C. van, Limbergen, E. van, Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K.M., Hunter, D.J., Lindstrom, S., Tamimi, R.M., Kraft, P., Rahman, N., Turnbull, C., Renwick, A., Seal, S., Li, J.M., Liu, J.J., Humphreys, K., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Anton-Culver, H., Neuhausen, S.L., Ziogas, A., Bernstein, L., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Cox, A., Cross, S.S., Reed, M.W.R., Khusnutdinova, E., Bermisheva, M., Prokofyeva, D., Takhirova, Z., Meindl, A., Schmutzler, R.K., Sutter, C., Yang, R.X., Schurmann, P., Bremer, M., Christiansen, H., Park-Simon, T.W., Hillemanns, P., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Radice, P., Peterlongo, P., Manoukian, S., Pensotti, V., Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Brauch, H., Bruning, T., Ko, Y.D., Sigurdson, A.J., Doody, M.M., Hamann, U., Torres, D., Ulmer, H.U., Forsti, A., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Chenevix-Trench, G., Balleine, R., Giles, G.G., Milne, R.L., McLean, C., Lindblom, A., Margolin, S., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Eilber, U., Wang-Gohrke, S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Koppert, L.B., Carpenter, J., Clarke, C., Scott, R., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Brenner, H., Arndt, V., Stegmaier, C., Dieffenbach, A.K., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Offit, K., Vijai, J., Robson, M., Rau-Murthy, R., Dwek, M., Swann, R., Perkins, K.A., Goldberg, M.S., Labreche, F., Dumont, M., Eccles, D.M., Tapper, W.J., Rafiq, S., John, E.M., Whittemore, A.S., Slager, S., Yannoukakos, D., Toland, A.E., Yao, S., Zheng, W., Halverson, S.L., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Simard, J., Hall, P., Easton, D.F., Garcia-Closas, M., Clinical Genetics, Medical Oncology, Surgery, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, HUS Gynecology and Obstetrics, Mavaddat, Nasim [0000-0003-0307-055X], Pharoah, Paul [0000-0001-8494-732X], Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, Genotype, 3122 Cancers, Breast Neoplasms, consortium, Polymorphism, Single Nucleotide, Risk Assessment, Article, prevention, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Risk Factors, 3123 Gynaecology and paediatrics, Biomarkers, Tumor, Odds Ratio, Humans, Genetic Predisposition to Disease, family-history, Aged, prostate, Gene Expression Profiling, subtypes, Middle Aged, susceptibility loci, Europe, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Tumor Markers, Biological, Cancer and Oncology, genome-wide association, Female, women
Abstract: Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1 of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. © 2015 © The Author 2015. Published by Oxford University Press.
Published: 2015

28. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Author: Orr, N., Dudbridge, F., Dryden, N., Maguire, S., Novo, D., Perrakis, E., Johnson, N., Ghoussaini, M., Hopper, J.L., Southey, M.C., Apicella, C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Hogervorst, F.B., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Gibson, L., Aitken, Z., Warren, H., Sawyer, E., Tomlinson, I., Kerin, M.J., Miller, N., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Truong, T., Cordina-Duverger, E., Sanchez, M., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Anton-Culver, H., Neuhausen, S.L., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Hamann, U., Brauch, H., Justenhoven, C., Bruning, T., Ko, Y.D., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Bogdanova, N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Chenevix-Trench, G., Beesley, J., Lambrechts, D., Moisse, M., Floris, G., Beuselinck, B., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Peissel, B., Pensotti, V., Couch, F.J., Olson, J.E., Slettedahl, S., Vachon, C., Giles, G.G., Milne, R.L., McLean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C.M., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Chanock, S.J., Lissowska, J., Czene, K., Darabi, H., Eriksson, M., Klevebring, D., Hooning, M.J., Hollestelle, A., Deurzen, C.H.M. van, Kriege, M., Hall, P., Li, J.M., Liu, J.J., Humphreys, K., Cox, A., Cross, S.S., Reed, M.W.R., Pharoah, P.D.P., Dunning, A.M., Shah, M., Perkins, B.J., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Ashworth, A., Swerdlow, A., Jones, M., Schoemaker, M.J., Meindl, A., Schmutzler, R.K., Olswold, C., Slager, S., Toland, A.E., Yannoukakos, D., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Matsuo, K., Ito, H., Iwata, H., Ishiguro, J., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Teo, S.H., Yip, C.H., Kang, P., Ikram, M.K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Hartman, M., Miao, H., Lim, W.Y., Lee, S.C., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Wu, P.E., Hou, M.F., Yu, J.C., Shen, C.Y., Blot, W., Cai, Q.Y., Signorello, L.B., Luccarini, C., Bayes, C., Ahmed, S., Maranian, M., Healey, C.S., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Hunter, D.J., Lindstrom, S., Dennis, J., Michailidou, K., Bolla, M.K., Easton, D.F., Silva, I.D., Fletcher, O., Peto, J., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Obstetrics & Gynecology, Medical Oncology, Pathology, Ophthalmology, Cardiothoracic Surgery, and Clinical Genetics
Subjects: Asian Continental Ancestry Group, Adult, Hepatocyte Nuclear Factor 3-alpha, Risk, binding, European Continental Ancestry Group, Kruppel-Like Transcription Factors, estrogen-receptor-alpha, Breast Neoplasms, GATA3 Transcription Factor, Polymorphism, Single Nucleotide, White People, Kruppel-Like Factor 4, Asian People, SDG 3 - Good Health and Well-being, Medizinische Fakultät, common variants, expression, Humans, Genetic Predisposition to Disease, ddc:610, Genetic Association Studies, Aged, Association Studies Articles, Estrogen Receptor alpha, Chromosome Mapping, foxa1, Middle Aged, confer susceptibility, analyses reveal, Enhancer Elements, Genetic, risk locus, Genetic Loci, functional variants, genome-wide association, Female, Chromosomes, Human, Pair 9
Abstract: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. ispartof: Human Molecular Genetics vol:24 issue:10 pages:2966-84 ispartof: location:England status: published
Published: 2015

29. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author: Milne, R.L., Burwinkel, B., Michailidou, K., Arias-Perez, J.I., Zamora, M.P., Menendez-Rodriguez, P., Hardisson, D., Mendiola, M., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Dennis, J., Wang, Q., Bolla, M.K., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M., Ko, Y.D., Brauch, H., Hamann, U., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Li, J.M., Brand, J.S., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Lambrechts, D., Peuteman, G., Christiaens, M.R., Smeets, A., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hartman, M., Hui, M., Lim, W.Y., Chan, C.W., Marme, F., Yang, R.X., Bugert, P., Lindblom, A., Margolin, S., Garcia-Closas, M., Chanock, S.J., Lissowska, J., Figueroa, J.D., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Hooning, M.J., Kriege, M., Ouweland, A.M.W. van den, Koppert, L.B., Fletcher, O., Johnson, N., Dos-Santos-Silva, I., Peto, J., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Cox, A., Cross, S.S., Reed, M.W.R., Schmidt, M.K., Broeks, A., Cornelissen, S., Braaf, L., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Simard, J., Dumont, M., Goldberg, M.S., Labreche, F., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Radice, P., Peterlongo, P., Azzollini, J., Barile, M., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Hopper, J.L., Schmidt, D.F., Makalic, E., Southey, M.C., Teo, S.H., Yip, C.H., Sivanandan, K., Tay, W.T., Shen, C.Y., Hsiung, C.N., Yu, J.C., Hou, M.F., Guenel, P., Truong, T., Sanchez, M., Mulot, C., Blot, W., Cai, Q.Y., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Bogdanova, N., Dork, T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Shu, X.O., Lu, W., Gao, Y.T., Zhang, B., Couch, F.J., Toland, A.E., Yannoukakos, D., Sangrajrang, S., McKay, J., Wang, X.S., Olson, J.E., Vachon, C., Purrington, K., Severi, G., Baglietto, L., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Czene, K., Eriksson, M., Humphreys, K., Darabi, H., Ahmed, S., Shah, M., Pharoah, P.D.P., Hall, P., Giles, G.G., Benitez, J., Dunning, A.M., Chenevix-Trench, G., Easton, D.F., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, TNBCC, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, Ataxin-7, A Kinase Anchor Proteins, Breast Neoplasms, Nerve Tissue Proteins, Middle Aged, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Cytoskeletal Proteins, Case-Control Studies, Humans, NIMA-Related Kinases, Female, Genetic Predisposition to Disease, health care economics and organizations, Alleles, Genome-Wide Association Study
Abstract: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility\ud variants, although most studies have been underpowered to detect associations of a realistic magnitude.\ud We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which\ud evidence of association with breast cancer risk had been previously reported. Case-control data were combined\ud from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional\ud logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21\ud [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04–1.10, P 5 2.9 3 1026\ud ], AKAP9-M463I at\ud 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03–1.07, P 5 1.7 3 1026\ud ) and NEK10-L513S at 3p24 (rs10510592,\ud OR 5 1.10, 95% CI 5 1.07 –1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical\ud significance in a combined analysis of available data, including independent data from nine genome-wide association\ud studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05–1.10, P 5 1.0 3 1028\ud ); for AKAP9-M463I,\ud OR 5 1.05 (95% CI 5 1.04–1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two\ud regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified\ud a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is\ud associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility\ud region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of\ud the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast\ud cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying\ud variants and the genes through which they act.
Published: 2014

30. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

Author: Rudolph, A., Milne, R. L., Truong, T., Knight, J. A., Seibold, P., Flesch-Janys, D., Behrens, S., Eilber, U., Bolla, M. K., Wang, Q., Dennis, J., Dunning, A. M., Shah, M., Munday, H. R., Darabi, H., Eriksson, M., Brand, J. S., Olson, J., Vachon, C. M., Hallberg, E., Castelao, J. E., Carracedo, A., Torres, M., Li, J., Humphreys, K., Cordina-Duverger, E., Menegaux, F., Flyger, H., Nordestgaard, B. G., Nielsen, S. F., Yesilyurt, B. T., Floris, G., Leunen, K., Engelhardt, E. G., Broeks, A., Rutgers, E. J., Glendon, G., Mulligan, A. M., Cross, S., Reed, M., Gonzalez-Neira, A., Perez, J. I. A., Provenzano, E., Apicella, C., Southey, M. C., Spurdle, A., Häberle, L., Beckmann, M. W., Ekici, A. B., Dieffenbach, A. K., Arndt, V., Stegmaier, C., McLean, C., Baglietto, L., Chanock, S. J., Lissowska, J., Sherman, M. E., Brüning, T., Hamann, U., Ko, Y. D., Orr, N., Schoemaker, M., Ashworth, A., Kosma, V. M., Kataja, V., Hartikainen, J. M., Mannermaa, A., Swerdlow, A., Giles, G. G., Brenner, H., Fasching, P. A., Chenevix-Trench, G., Hopper, J., Benítez, J., Cox, A., Andrulis, I. L., Lambrechts, D., Gago-Dominguez, M., Couch, F., Czene, K., Bojesen, S. E., Easton, D. F., Schmidt, M. K., Guénel, P., Hall, P., Pharoah, P. D. P., Garcia-Closas, M., Chang-Claude, J., and Other departments
Subjects: Cancer Research, Medicine (all), Breast cancer, Gene-environment interaction, Genetic susceptibility, Risk factor, Oncology, Breast Neoplasms, Polymorphism, Single Nucleotide, Article, Receptors, Estrogen, Genetic Loci, Risk Factors, Humans, Female, Gene-Environment Interaction, Genetic Predisposition to Disease
Abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (p(int))
Published: 2014

31. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium

Author: Rl, Milne, Herranz J, Michailidou K, Joe Dennis, Jp, Tyrer, Mp, Zamora, Ji, Arias-Perez, González-Neira A, Pita G, Alonso MR, Wang Q, Mk, Bolla, Czene K, Eriksson M, Humphreys K, Darabi H, Li J, Anton-Culver H, Sl, Neuhausen, Ziogas A, Ca, Clarke, Jl, Hopper, Gs, Dite, Apicella C, Mc, Southey, Chenevix-Trench G, kConFab Investigators, Australian Ovarian Cancer Study Group, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Il, Andrulis, Ja, Knight, Glendon G, Am, Mulligan, Se, Bojesen, Bg, Nordestgaard, Flyger H, Nevanlinna H, Ta, Muranen, Aittomäki K, Blomqvist C, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Je, Olson, Vachon C, Purrington K, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Am, Dunning, Shah M, Guénel P, Truong T, Sanchez M, Mulot C, Brenner H, Ak, Dieffenbach, Arndt V, Stegmaier C, Lindblom A, Margolin S, Hooning M, Hollestelle A, Collée M, Jager A, Cox A, Iw, Brock, Mw, Reed, Devilee P, Ra, Tollenaar, Seynaeve C, Ca, Haiman, Be, Henderson, Schumacher F, Le Marchand L, Simard J, Dumont M, Soucy P, Dörk T, Nv, Bogdanova, Hamann U, Försti A, Rüdiger T, Hu, Ulmer, Pa, Fasching, Häberle L, Ab, Ekici, Mw, Beckmann, Fletcher O, Johnson N, Id, Silva, Peto J, Radice P, Peterlongo P, Peissel B, Mariani P, Gg, Giles, Severi G, Baglietto L, Sawyer E, Tomlinson I, Kerin M, Miller N, Marme F, Burwinkel B, Mannermaa A, Kataja V, Vm, Kosma, Hartikainen J, Lambrechts D, Bt, Yesilyurt, Floris G, Leunen K, Gg, Alnæs, Kristensen V, Al, Børresen-Dale, García-Closas M, Sj, Chanock, Lissowska J, Jd, Figueroa, Mk, Schmidt, Broeks A, Verhoef S, Ej, Rutgers, Brauch H, Brüning T, Yd, Ko, Genica, The Network, Fj, Couch, Ae, Toland, Tnbcc, The, Yannoukakos D, Pd, Pharoah, Hall P, Benítez J, Malats N, and Df, Easton
Subjects: Australian Ovarian Cancer Study Group, Genetics & Heredity, Breast Neoplasms, Epistasis, Genetic, Biological Sciences, TNBCC, Polymorphism, Single Nucleotide, Medical and Health Sciences, Logistic Models, Case-Control Studies, kConFab Investigators, Humans, Genetic Predisposition to Disease, Female, GENICA Network, Genome-Wide Association Study
Abstract: Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
Published: 2014

32. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Author: Michailidou, K., Hall, P., Gonzalez-Neira, A., Ghoussaini, M., Dennis, J., Milne, R.L., Schmidt, M.K., Chang-Claude, J., Bojesen, S.E., Bolla, M.K., Wang, Q., Dicks, E., Lee, A., Turnbull, C., Rahman, N., Fletcher, O., Peto, J., Gibson, L., Silva, I.D., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Czene, K., Irwanto, A., Liu, J.J., Waisfisz, Q., Meijers-Heijboer, H., Adank, M., Luijt, R.B. van der, Hein, R., Dahmen, N., Beckman, L., Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Hopper, J.L., Southey, M.C., Makalic, E., Schmidt, D.F., Uitterlinden, A.G., Hofman, A., Hunter, D.J., Chanock, S.J., Vincent, D., Bacot, F., Tessier, D.C., Canisius, S., Wessels, L.F.A., Haiman, C.A., Shah, M., Luben, R., Brown, J., Luccarini, C., Schoof, N., Humphreys, K., Li, J.M., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Couch, F.J., Wang, X.S., Vachon, C., Stevens, K.N., Lambrechts, D., Moisse, M., Paridaens, R., Christiaens, M.R., Rudolph, A., Nickels, S., Flesch-Janys, D., Johnson, N., Aitken, Z., Aaltonen, K., Heikkinen, T., Broeks, A., Van't Veer, L.J., Schoot, C.E. van der, Guenel, P., Truong, T., Laurent-Puig, P., Menegaux, F., Marme, F., Schneeweiss, A., Sohn, C., Burwinke, B., Zamora, M.P., Perez, J.I.A., Pita, G., Alonso, M.R., Cox, A., Brock, I.W., Cross, S.S., Reed, M.W.R., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Henderson, B.E., Schumacher, F., Marchand, L. le, Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Lindblom, A., Margolin, S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Bui, Q.M., Stone, J., Dite, G.S., Apicella, C., Tsimiklis, H., Giles, G.G., Severi, G., Baglietto, L., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Brenner, H., Muller, H., Arndt, V., Stegmaier, C., Swerdlown, A., Ashworth, A., Orr, N., Jones, M., Figueroa, J., Lissowska, J., Brinton, L., Goldberg, M.S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Bruning, T., Radice, P., Peterlongo, P., Manouldan, S., Bonanni, B., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Kristensen, V.N., Anton-Culver, H., Slager, S., Toland, A.E., Edge, S., Fostira, F., Kang, D., Yoo, K.Y., Noh, D.Y., Matsuo, K., Ito, H., Iwata, H., Sueta, A., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Teo, S.H., Yip, C.H., Phuah, S.Y., Cornes, B.K., Hartman, M., Miao, H., Lim, W.Y., Sng, J.H., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Blot, W.J., Signorello, L.B., Cai, Q.Y., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Simard, J., Garcia-Closas, M., Pharoah, P.D.P., Chenevix-Trench, G., Dunning, A.M., Benitez, J., Easton, D.F., Breast Ovarian Canc Susceptibility, Hereditary Breast Ovarian Canc Res, kConFab Investigators, Australian Ovarian Can Study Grp, GENICA Gene Environm Interaction B, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Landsteiner Laboratory, Clinical Haematology, Clinical Genetics, Internal Medicine, Epidemiology, Medical Oncology, Cardiothoracic Surgery, Human genetics, CCA - Oncogenesis, and ~
Subjects: signaling pathway, Genotyping, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, consortium, Biology, Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genetic Loci, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors, Genetic Predisposition to Disease, Genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, common variants, expression, medicine, Polymorphism, gene, hormone-related protein, 030304 developmental biology, Genetic association, 0303 health sciences, Breast cancer susceptibility, Cancer, Single Nucleotide, medicine.disease, confer susceptibility, susceptibility loci, 3. Good health, 14q24.1 rad51l1, TOX3, 030220 oncology & carcinogenesis, genome-wide association
Abstract: Journal article Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10!¿8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. European Community Seventh Framework Programme - grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) peer-reviewed
Published: 2013

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32 results on '"Stegmaier C."'

1. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

2. Discovery of common and rare genetic risk variants for colorectal cancer.

3. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

4. Association analysis identifies 65 new breast cancer risk loci.

5. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

6. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

7. Prediction of individual genetic risk to prostate cancer using a polygenic score.

8. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

9. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

10. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.

11. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

12. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

13. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

14. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

15. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium.

16. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

17. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions.

18. Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

19. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

20. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus.

21. Genome-wide association analysis identifies three new breast cancer susceptibility loci.

22. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

23. Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

24. Testicular, other genital, and breast cancers in first-degree relatives of testicular cancer patients and controls.

25. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

26. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

27. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

28. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

29. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

30. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

31. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium

32. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

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32 results on '"Stegmaier C."'

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