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1. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author

Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chornokur G, Earp MA, Lyra PC Jr, Lee JM, Coetzee S, Beesley J, McGuffog L, Soucy P, Dicks E, Lee A, Barrowdale D, Lecarpentier J, Leslie G, Aalfs CM, Aben KKH, Adams M, Adlard J, Andrulis IL, Anton-Culver H, Antonenkova N, Aravantinos G, Arnold N, Arun BK, Arver B, Azzollini J, Balmaña J, Banerjee SN, Barjhoux L, Barkardottir RB, Bean Y, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Birrer MJ, Bjorge L, Black A, Blankstein K, Blok MJ, Bodelon C, Bogdanova N, Bojesen A, Bonanni B, Borg Å, Bradbury AR, Brenton JD, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Bruinsma F, Brunet J, Buecher B, Butzow R, Buys SS, Caldes T, Caligo MA, Campbell I, Cannioto R, Carney ME, Cescon T, Chan SB, Chang-Claude J, Chanock S, Chen XQ, Chiew YE, Chiquette J, Chung WK, Claes KBM, Conner T, Cook LS, Cook J, Cramer DW, Cunningham JM, D'Aloisio AA, Daly MB, Damiola F, Damirovna SD, Dansonka-Mieszkowska A, Dao F, Davidson R, DeFazio A, Delnatte C, Doheny KF, Diez O, Ding YC, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dossus L, Duran M, Dürst M, Dworniczak B, Eccles D, Edwards T, Eeles R, Eilber U, Ejlertsen B, Ekici AB, Ellis S, Elvira M, Eng KH, Engel C, Evans DG, Fasching PA, Ferguson S, Ferrer SF, Flanagan JM, Fogarty ZC, Fortner RT, Fostira F, Foulkes WD, Fountzilas G, Fridley BL, Friebel TM, Friedman E, Frost D, Ganz PA, Garber J, García MJ, Garcia-Barberan V, Gehrig A, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goldgar DE, Goranova T, Gore M, Greene MH, Gronwald J, Gruber S, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TVO, Harrington PA, Harris HR, Hauke J, Hein A, Henderson A, Hildebrandt MAT, Hillemanns P, Hodgson S, Høgdall CK, Høgdall E, Hogervorst FBL, Holland H, Hooning MJ, Hosking K, Huang RY, Hulick PJ, Hung J, Hunter DJ, Huntsman DG, Huzarski T, Imyanitov EN, Isaacs C, Iversen ES, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jernetz M, Jensen A, Jensen UB, John EM, Johnatty S, Jones ME, Kannisto P, Karlan BY, Karnezis A, Kast K, Kennedy CJ, Khusnutdinova E, Kiemeney LA, Kiiski JI, Kim SW, Kjaer SK, Köbel M, Kopperud RK, Kruse TA, Kupryjanczyk J, Kwong A, Laitman Y, Lambrechts D, Larrañaga N, Larson MC, Lazaro C, Le ND, Le Marchand L, Lee JW, Lele SB, Leminen A, Leroux D, Lester J, Lesueur F, Levine DA, Liang D, Liebrich C, Lilyquist J, Lipworth L, Lissowska J, Lu KH, Lubinński J, Luccarini C, Lundvall L, Mai PL, Mendoza-Fandiño G, Manoukian S, Massuger LFAG, May T, Mazoyer S, McAlpine JN, McGuire V, McLaughlin JR, McNeish I, Meijers-Heijboer H, Meindl A, Menon U, Mensenkamp AR, Merritt MA, Milne RL, Mitchell G, Modugno F, Moes-Sosnowska J, Moffitt M, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Nathanson KL, Nedergaard L, Ness RB, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Odunsi K, Olah E, Olopade OI, Olsson H, Olswold C, O'Malley DM, Ong KR, Onland-Moret NC, Orr N, Orsulic S, Osorio A, Palli D, Papi L, Park-Simon TW, Paul J, Pearce CL, Pedersen IS, Peeters PHM, Peissel B, Peixoto A, Pejovic T, Pelttari LM, Permuth JB, Peterlongo P, Pezzani L, Pfeiler G, Phillips KA, Piedmonte M, Pike MC, Piskorz AM, Poblete SR, Pocza T, Poole EM, Poppe B, Porteous ME, Prieur F, Prokofyeva D, Pugh E, Pujana MA, Pujol P, Radice P, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rhiem K, Rice P, Richardson A, Robson M, Rodriguez GC, Rodríguez-Antona C, Romm J, Rookus MA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Salvesen HB, Sandler DP, Schoemaker MJ, Senter L, Setiawan VW, Severi G, Sharma P, Shelford T, Siddiqui N, Side LE, Sieh W, Singer CF, Sobol H, Song H, Southey MC, Spurdle AB, Stadler Z, Steinemann D, Stoppa-Lyonnet D, Sucheston-Campbell LE, Sukiennicki G, Sutphen R, Sutter C, Swerdlow AJ, Szabo CI, Szafron L, Tan YY, Taylor JA, Tea MK, Teixeira MR, Teo SH, Terry KL, Thompson PJ, Thomsen LCV, Thull DL, Tihomirova L, Tinker AV, Tischkowitz M, Tognazzo S, Toland AE, Tone A, Trabert B, Travis RC, Trichopoulou A, Tung N, Tworoger SS, van Altena AM, Van Den Berg D, van der Hout AH, van der Luijt RB, Van Heetvelde M, Van Nieuwenhuysen E, van Rensburg EJ, Vanderstichele A, Varon-Mateeva R, Vega A, Edwards DV, Vergote I, Vierkant RA, Vijai J, Vratimos A, Walker L, Walsh C, Wand D, Wang-Gohrke S, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, Whittemore AS, Wijnen JT, Wilkens LR, Wolk A, Woo M, Wu X, Wu AH, Yang H, Yannoukakos D, Ziogas A, Zorn KK, Narod SA, Easton DF, Amos CI, Schildkraut JM, Ramus SJ, Ottini L, Goodman MT, Park SK, Kelemen LE, Risch HA, Thomassen M, Offit K, Simard J, Schmutzler RK, Hazelett D, Monteiro AN, Couch FJ, Berchuck A, Chenevix-Trench G, Goode EL, Sellers TA, Gayther SA, Antoniou AC, and Pharoah PDP

Subjects
Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Mutation, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Risk Factors, Telomere-Binding Proteins genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017
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2. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

Author

Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, Hillemanns P, Preus L, Knutson KL, Wallace PK, Hong CC, Friel G, Davis W, Nesline M, Pearce CL, Kelemen LE, Goodman MT, Bandera EV, Terry KL, Schoof N, Eng KH, Clay A, Singh PK, Joseph JM, Aben KK, Anton-Culver H, Antonenkova N, Baker H, Bean Y, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Cook LS, Cramer DW, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Despierre E, Dicks E, Doherty JA, du Bois A, Dürst M, Easton D, Eccles D, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Gronwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hogdall C, Hogdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Karlan BY, Kellar M, Kelley JL, Kiemeney LA, Klapdor R, Kolomeyevskaya N, Krakstad C, Kjaer SK, Kruszka B, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Liu S, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Moes-Sosnowska J, Narod SA, Nedergaard L, Nevanlinna H, Nickels S, Olson SH, Orlow I, Weber RP, Paul J, Pejovic T, Pelttari LM, Perkins B, Permuth-Wey J, Pike MC, Plisiecka-Halasa J, Poole EM, Risch HA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schernhammer E, Schmitt K, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Tangen IL, Teo SH, Thompson PJ, Timorek A, Tsai YY, Tworoger SS, Tyrer J, van Altena AM, Vergote I, Vierkant RA, Walsh C, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Woo YL, Yang H, Zheng W, Ziogas A, Gayther SA, Ramus SJ, Sellers TA, Schildkraut JM, Phelan CM, Berchuck A, Chenevix-Trench G, Cunningham JM, Pharoah PP, Ness RB, Odunsi K, Goode EL, and Moysich KB

Subjects
Adenocarcinoma, Clear Cell immunology, Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genotype, Humans, Middle Aged, Neoplasms, Glandular and Epithelial immunology, Ovarian Neoplasms immunology, Receptor, Transforming Growth Factor-beta Type II, Risk Factors, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Adenocarcinoma, Clear Cell genetics, Genetic Predisposition to Disease genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases genetics, Receptors, Transforming Growth Factor beta genetics
Abstract

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer., Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients., Results: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively)., Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016
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3. Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci.

Author

Clyde MA, Palmieri Weber R, Iversen ES, Poole EM, Doherty JA, Goodman MT, Ness RB, Risch HA, Rossing MA, Terry KL, Wentzensen N, Whittemore AS, Anton-Culver H, Bandera EV, Berchuck A, Carney ME, Cramer DW, Cunningham JM, Cushing-Haugen KL, Edwards RP, Fridley BL, Goode EL, Lurie G, McGuire V, Modugno F, Moysich KB, Olson SH, Pearce CL, Pike MC, Rothstein JH, Sellers TA, Sieh W, Stram D, Thompson PJ, Vierkant RA, Wicklund KG, Wu AH, Ziogas A, Tworoger SS, and Schildkraut JM

Subjects
Adult, Aged, Area Under Curve, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide, Risk Assessment methods, Risk Factors, United States, Genetic Loci genetics, Logistic Models, Neoplasms, Glandular and Epithelial etiology, Ovarian Neoplasms etiology
Abstract

Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2016
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4. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Author

Ong JS, Cuellar-Partida G, Lu Y, Fasching PA, Hein A, Burghaus S, Beckmann MW, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Vanderstichele A, Anne Doherty J, Anne Rossing M, Chang-Claude J, Eilber U, Rudolph A, Wang-Gohrke S, Goodman MT, Bogdanova N, Dörk T, Dürst M, Hillemanns P, Runnebaum IB, Antonenkova N, Butzow R, Leminen A, Nevanlinna H, Pelttari LM, Edwards RP, Kelley JL, Modugno F, Moysich KB, Ness RB, Cannioto R, Høgdall E, Høgdall CK, Jensen A, Giles GG, Bruinsma F, Kjaer SK, Hildebrandt MA, Liang D, Lu KH, Wu X, Bisogna M, Dao F, Levine DA, Cramer DW, Terry KL, Tworoger SS, Stampfer M, Missmer S, Bjorge L, Salvesen HB, Kopperud RK, Bischof K, Aben KK, Kiemeney LA, Massuger LF, Brooks-Wilson A, Olson SH, McGuire V, Rothstein JH, Sieh W, Whittemore AS, Cook LS, Le ND, Gilks CB, Gronwald J, Jakubowska A, Lubiński J, Kluz T, Song H, Tyrer JP, Wentzensen N, Brinton L, Trabert B, Lissowska J, McLaughlin JR, Narod SA, Phelan C, Anton-Culver H, Ziogas A, Eccles D, Campbell I, Gayther SA, Gentry-Maharaj A, Menon U, Ramus SJ, Wu AH, Dansonka-Mieszkowska A, Kupryjanczyk J, Timorek A, Szafron L, Cunningham JM, Fridley BL, Winham SJ, Bandera EV, Poole EM, Morgan TK, Risch HA, Goode EL, Schildkraut JM, Pearce CL, Berchuck A, Pharoah PD, Chenevix-Trench G, Gharahkhani P, Neale RE, Webb PM, and MacGregor S

Subjects
Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Neoplasms, Glandular and Epithelial genetics, Odds Ratio, Ovarian Neoplasms genetics, Risk Factors, Vitamin D blood, Mendelian Randomization Analysis, Neoplasms, Glandular and Epithelial blood, Neoplasms, Glandular and Epithelial epidemiology, Ovarian Neoplasms blood, Ovarian Neoplasms epidemiology, Polymorphism, Single Nucleotide, Vitamin D analogs & derivatives
Abstract

Background: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer., Methods: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases)., Results: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01)., Conclusions: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Published
2016
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5. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Author

Cuellar-Partida G, Lu Y, Dixon SC, Fasching PA, Hein A, Burghaus S, Beckmann MW, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Vanderstichele A, Doherty JA, Rossing MA, Chang-Claude J, Rudolph A, Wang-Gohrke S, Goodman MT, Bogdanova N, Dörk T, Dürst M, Hillemanns P, Runnebaum IB, Antonenkova N, Butzow R, Leminen A, Nevanlinna H, Pelttari LM, Edwards RP, Kelley JL, Modugno F, Moysich KB, Ness RB, Cannioto R, Høgdall E, Høgdall C, Jensen A, Giles GG, Bruinsma F, Kjaer SK, Hildebrandt MA, Liang D, Lu KH, Wu X, Bisogna M, Dao F, Levine DA, Cramer DW, Terry KL, Tworoger SS, Stampfer M, Missmer S, Bjorge L, Salvesen HB, Kopperud RK, Bischof K, Aben KK, Kiemeney LA, Massuger LF, Brooks-Wilson A, Olson SH, McGuire V, Rothstein JH, Sieh W, Whittemore AS, Cook LS, Le ND, Blake Gilks C, Gronwald J, Jakubowska A, Lubiński J, Kluz T, Song H, Tyrer JP, Wentzensen N, Brinton L, Trabert B, Lissowska J, McLaughlin JR, Narod SA, Phelan C, Anton-Culver H, Ziogas A, Eccles D, Campbell I, Gayther SA, Gentry-Maharaj A, Menon U, Ramus SJ, Wu AH, Dansonka-Mieszkowska A, Kupryjanczyk J, Timorek A, Szafron L, Cunningham JM, Fridley BL, Winham SJ, Bandera EV, Poole EM, Morgan TK, Goode EL, Schildkraut JM, Pearce CL, Berchuck A, Pharoah PD, Webb PM, Chenevix-Trench G, Risch HA, and MacGregor S

Subjects
Carcinoma, Ovarian Epithelial, Female, Humans, Neoplasms, Glandular and Epithelial classification, Ovarian Neoplasms classification, Polymorphism, Single Nucleotide genetics, Genotype, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Pathology, Molecular
Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Published
2016
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6. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

Author

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

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

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

Published
2016
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7. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

Author

Amankwah EK, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Chornokur G, Aben KK, Anton-Culver H, Antonenkova N, Bruinsma F, Bandera EV, Bean YT, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bunker CH, Butzow R, Campbell IG, Carty K, Chen Z, Chen YA, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, du Bois A, Despierre E, Dicks E, Doherty JA, Dörk T, Dürst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall CK, Hogdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Karlan BY, Jim H, Kellar M, Kiemeney LA, Krakstad C, Kjaer SK, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lim BK, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Milne RL, Modugno F, Moysich KB, Ness RB, Nevanlinna H, Eilber U, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Paul J, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Pike MC, Poole EM, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schernhammer E, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Spiewankiewicz B, Sucheston-Campbell L, Teo SH, Terry KL, Thompson PJ, Thomsen L, Tangen IL, Tworoger SS, van Altena AM, Vierkant RA, Vergote I, Walsh CS, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Woo YL, Yang H, Zheng W, Ziogas A, Kelemen LE, Berchuck A, Schildkraut JM, Ramus SJ, Goode EL, Monteiro AN, Gayther SA, Narod SA, Pharoah PD, Sellers TA, and Phelan CM

Subjects
Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Odds Ratio, Risk, White People, Epithelial-Mesenchymal Transition genetics, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial epidemiology, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide genetics
Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC., (© 2015 WILEY PERIODICALS, INC.)

Published
2015
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8. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Author

Lawrenson K, Iversen ES, Tyrer J, Weber RP, Concannon P, Hazelett DJ, Li Q, Marks JR, Berchuck A, Lee JM, Aben KK, Anton-Culver H, Antonenkova N, Bandera EV, Bean Y, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Chang-Claude J, Chenevix-Trench G, Chen A, Chen Z, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Plisiecka-Halasa J, Dennis J, Dicks E, Doherty JA, Dörk T, du Bois A, Eccles D, Easton DT, Edwards RP, Eilber U, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Gronwald J, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall E, Hogdall C, Hosono S, Jakubowska A, Paul J, Jensen A, Karlan BY, Kjaer SK, Kelemen LE, Kellar M, Kelley JL, Kiemeney LA, Krakstad C, Lambrechts D, Lambrechts S, Le ND, Lee AW, Cannioto R, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, Nevanlinna H, McNeish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Noor Azmi MA, Odunsi K, Olson SH, Orlow I, Orsulic S, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Ramus SJ, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Budzilowska A, Sellers TA, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo SH, Terry KL, Thompson PJ, Timorek A, Tworoger SS, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo YL, Wu X, Wu AH, Yang H, Zheng W, Ziogas A, Coetzee GA, Freedman ML, Monteiro AN, Moes-Sosnowska J, Kupryjanczyk J, Pharoah PD, Gayther SA, and Schildkraut JM

Subjects
Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Checkpoint Kinase 2 genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene., (© 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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9. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Author

Lawrenson K, Li Q, Kar S, Seo JH, Tyrer J, Spindler TJ, Lee J, Chen Y, Karst A, Drapkin R, Aben KK, Anton-Culver H, Antonenkova N, Baker H, Bandera EV, Bean Y, Beckmann MW, Berchuck A, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Chang-Claude J, Chenevix-Trench G, Chen A, Chen Z, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles D, Easton DT, Edwards RP, Eilber U, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Grownwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall E, Hogdall C, Hosono S, Iversen ES, Jakubowska A, James P, Jensen A, Ji BT, Karlan BY, Kruger Kjaer S, Kelemen LE, Kellar M, Kelley JL, Kiemeney LA, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, Nevanlinna H, McNeish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Azmi MA, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Ramus SJ, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schildkraut JM, Schwaab I, Sellers TA, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo SH, Terry KL, Thompson PJ, Timorek A, Tsai YY, Tworoger SS, van Altena AM, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo YL, Wu X, Wu AH, Yang H, Zheng W, Ziogas A, Monteiro A, Pharoah PD, Gayther SA, and Freedman ML

Subjects
Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Neoplasm Proteins metabolism, Neoplasms, Glandular and Epithelial metabolism, Nuchal Cord, Ovarian Neoplasms metabolism, Protein Binding, Genetic Association Studies, Neoplasm Proteins genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Quantitative Trait Loci
Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Published
2015
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10. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Author

Chornokur G, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Amankwah EK, Qu X, Tsai YY, Jim HS, Chen Z, Chen AY, Permuth-Wey J, Aben KK, Anton-Culver H, Antonenkova N, Bruinsma F, Bandera EV, Bean YT, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bunker CH, Butzow R, Campbell IG, Carty K, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, du Bois A, Despierre E, Dicks E, Doherty JA, Dörk T, Dürst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harrington P, Harter P, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall CK, Hogdall E, Hosono S, Jakubowska A, Jensen A, Ji BT, Karlan BY, Kelemen LE, Kellar M, Kiemeney LA, Krakstad C, Kjaer SK, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lim BK, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Milne RL, Modugno F, Moysich KB, Ness RB, Nevanlinna H, Eilber U, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Paul J, Pearce CL, Pejovic T, Pelttari LM, Pike MC, Poole EM, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schernhammer E, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Spiewankiewicz B, Sucheston L, Teo SH, Terry KL, Thompson PJ, Thomsen L, Tangen IL, Tworoger SS, van Altena AM, Vierkant RA, Vergote I, Walsh CS, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Woo YL, Yang H, Zheng W, Ziogas A, Hasmad HN, Berchuck A, Iversen ES, Schildkraut JM, Ramus SJ, Goode EL, Monteiro AN, Gayther SA, Narod SA, Pharoah PD, Sellers TA, and Phelan CM

Subjects
Black or African American, Alleles, Asian, Biological Transport, Carcinoma, Ovarian Epithelial, Carrier Proteins metabolism, Case-Control Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Neoplasms, Glandular and Epithelial pathology, Odds Ratio, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Carrier Proteins genetics, Genetic Variation, Neoplasms, Glandular and Epithelial epidemiology, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Risk
Abstract

Background: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk., Methods: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons., Results: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4)., Conclusion: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Published
2015
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11. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Author

Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, Lawrenson K, McGuffog L, Healey S, Lee JM, Spindler TJ, Lin YG, Pejovic T, Bean Y, Li Q, Coetzee S, Hazelett D, Miron A, Southey M, Terry MB, Goldgar DE, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Neuhausen SL, Ding YC, Hansen TV, Jønson L, Gerdes AM, Ejlertsen B, Barrowdale D, Dennis J, Benitez J, Osorio A, Garcia MJ, Komenaka I, Weitzel JN, Ganschow P, Peterlongo P, Bernard L, Viel A, Bonanni B, Peissel B, Manoukian S, Radice P, Papi L, Ottini L, Fostira F, Konstantopoulou I, Garber J, Frost D, Perkins J, Platte R, Ellis S, Godwin AK, Schmutzler RK, Meindl A, Engel C, Sutter C, Sinilnikova OM, Damiola F, Mazoyer S, Stoppa-Lyonnet D, Claes K, De Leeneer K, Kirk J, Rodriguez GC, Piedmonte M, O'Malley DM, de la Hoya M, Caldes T, Aittomäki K, Nevanlinna H, Collée JM, Rookus MA, Oosterwijk JC, Tihomirova L, Tung N, Hamann U, Isaccs C, Tischkowitz M, Imyanitov EN, Caligo MA, Campbell IG, Hogervorst FB, Olah E, Diez O, Blanco I, Brunet J, Lazaro C, Pujana MA, Jakubowska A, Gronwald J, Lubinski J, Sukiennicki G, Barkardottir RB, Plante M, Simard J, Soucy P, Montagna M, Tognazzo S, Teixeira MR, Pankratz VS, Wang X, Lindor N, Szabo CI, Kauff N, Vijai J, Aghajanian CA, Pfeiler G, Berger A, Singer CF, Tea MK, Phelan CM, Greene MH, Mai PL, Rennert G, Mulligan AM, Tchatchou S, Andrulis IL, Glendon G, Toland AE, Jensen UB, Kruse TA, Thomassen M, Bojesen A, Zidan J, Friedman E, Laitman Y, Soller M, Liljegren A, Arver B, Einbeigi Z, Stenmark-Askmalm M, Olopade OI, Nussbaum RL, Rebbeck TR, Nathanson KL, Domchek SM, Lu KH, Karlan BY, Walsh C, Lester J, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Lambrechts S, Dicks E, Doherty JA, Wicklund KG, Rossing MA, Rudolph A, Chang-Claude J, Wang-Gohrke S, Eilber U, Moysich KB, Odunsi K, Sucheston L, Lele S, Wilkens LR, Goodman MT, Thompson PJ, Shvetsov YB, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Pelttari LM, Butzow R, Modugno F, Kelley JL, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Matsuo K, Hosono S, Orsulic S, Jensen A, Kjaer SK, Hogdall E, Hasmad HN, Azmi MA, Teo SH, Woo YL, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Bruinsma F, Giles GG, Liang D, Hildebrandt MA, Wu X, Levine DA, Bisogna M, Berchuck A, Iversen ES, Schildkraut JM, Concannon P, Weber RP, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Orlow I, Olson SH, Krakstad C, Salvesen HB, Tangen IL, Bjorge L, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Kellar M, Brooks-Wilson A, Kelemen LE, Cook LS, Le ND, Cybulski C, Yang H, Lissowska J, Brinton LA, Wentzensen N, Hogdall C, Lundvall L, Nedergaard L, Baker H, Song H, Eccles D, McNeish I, Paul J, Carty K, Siddiqui N, Glasspool R, Whittemore AS, Rothstein JH, McGuire V, Sieh W, Ji BT, Zheng W, Shu XO, Gao YT, Rosen B, Risch HA, McLaughlin JR, Narod SA, Monteiro AN, Chen A, Lin HY, Permuth-Wey J, Sellers TA, Tsai YY, Chen Z, Ziogas A, Anton-Culver H, Gentry-Maharaj A, Menon U, Harrington P, Lee AW, Wu AH, Pearce CL, Coetzee G, Pike MC, Dansonka-Mieszkowska A, Timorek A, Rzepecka IK, Kupryjanczyk J, Freedman M, Noushmehr H, Easton DF, Offit K, Couch FJ, Gayther S, Pharoah PP, Antoniou AC, and Chenevix-Trench G

Subjects
Adolescent, Adult, Alleles, Carcinoma, Ovarian Epithelial, Female, Genes, Reporter, Genotype, Heterozygote, Humans, Mutation, Quantitative Trait Loci, Risk, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Published
2015
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12. Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Author

Block MS, Charbonneau B, Vierkant RA, Fogarty Z, Bamlet WR, Pharoah PD, Rossing MA, Cramer D, Pearce CL, Schildkraut J, Menon U, Kjaer SK, Levine DA, Gronwald J, Culver HA, Whittemore AS, Karlan BY, Lambrechts D, Wentzensen N, Kupryjanczyk J, Chang-Claude J, Bandera EV, Hogdall E, Heitz F, Kaye SB, Fasching PA, Campbell I, Goodman MT, Pejovic T, Bean YT, Hays LE, Lurie G, Eccles D, Hein A, Beckmann MW, Ekici AB, Paul J, Brown R, Flanagan JM, Harter P, du Bois A, Schwaab I, Hogdall CK, Lundvall L, Olson SH, Orlow I, Paddock LE, Rudolph A, Eilber U, Dansonka-Mieszkowska A, Rzepecka IK, Ziolkowska-Seta I, Brinton LA, Yang H, Garcia-Closas M, Despierre E, Lambrechts S, Vergote I, Walsh CS, Lester J, Sieh W, McGuire V, Rothstein JH, Ziogas A, Lubiński J, Cybulski C, Menkiszak J, Jensen A, Gayther SA, Ramus SJ, Gentry-Maharaj A, Berchuck A, Wu AH, Pike MC, Van Den Berg D, Terry KL, Vitonis AF, Ramirez SM, Rider DN, Knutson KL, Sellers TA, Phelan CM, Doherty JA, Johnatty SE, deFazio A, Song H, Tyrer J, Kalli KR, Fridley BL, Cunningham JM, and Goode EL

Subjects
Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Genotype, Humans, Middle Aged, Neoplasm Invasiveness, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Proportional Hazards Models, NF-kappa B genetics, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality, Signal Transduction genetics
Abstract

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies., (©2014 American Association for Cancer Research.)

Published
2014
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13. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Author

Earp MA, Kelemen LE, Magliocco AM, Swenerton KD, Chenevix-Trench G, Lu Y, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Despierre E, Vergote I, Lambrechts S, Doherty JA, Rossing MA, Chang-Claude J, Rudolph A, Friel G, Moysich KB, Odunsi K, Sucheston-Campbell L, Lurie G, Goodman MT, Carney ME, Thompson PJ, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Nevanlinna H, Pelttari LM, Butzow R, Bunker CH, Modugno F, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Karlan BY, Walsh C, Lester J, Jensen A, Kjær SK, Høgdall CK, Høgdall E, Lundvall L, Sellers TA, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Giles GG, Baglietto L, Severi G, Southey MC, Liang D, Wu X, Lu K, Hildebrandt MA, Levine DA, Bisogna M, Schildkraut JM, Iversen ES, Weber RP, Berchuck A, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Chandran U, Orlow I, Olson SH, Wik E, Salvesen HB, Bjorge L, Halle MK, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Pejovic T, Bean YT, Cybulski C, Gronwald J, Lubinski J, Wentzensen N, Brinton LA, Lissowska J, Garcia-Closas M, Dicks E, Dennis J, Easton DF, Song H, Tyrer JP, Pharoah PD, Eccles D, Campbell IG, Whittemore AS, McGuire V, Sieh W, Rothstein JH, Flanagan JM, Paul J, Brown R, Phelan CM, Risch HA, McLaughlin JR, Narod SA, Ziogas A, Anton-Culver H, Gentry-Maharaj A, Menon U, Gayther SA, Ramus SJ, Wu AH, Pearce CL, Pike MC, Dansonka-Mieszkowska A, Rzepecka IK, Szafron LM, Kupryjanczyk J, Cook LS, Le ND, and Brooks-Wilson A

Subjects
Carcinoma, Ovarian Epithelial, Female, Humans, Polymorphism, Single Nucleotide, Quality Control, Alleles, DNA genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Published
2014
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