Sir Peter MacCallum Department of Oncology - Research Publications

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Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

O'Mahony, DG ; Ramus, SJ ; Southey, MC ; Meagher, NS ; Hadjisavvas, A ; John, EM ; Hamann, U ; Imyanitov, EN ; Andrulis, IL ; Sharma, P ; Daly, MB ; Hake, CR ; Weitzel, JN ; Jakubowska, A ; Godwin, AK ; Arason, A ; Bane, A ; Simard, J ; Soucy, P ; Caligo, MA ; Mai, PL ; Claes, KBM ; Teixeira, MR ; Chung, WK ; Lazaro, C ; Hulick, PJ ; Toland, AE ; Pedersen, IS ; Neuhausen, SL ; Vega, A ; de la Hoya, M ; Nevanlinna, H ; Dhawan, M ; Zampiga, V ; Danesi, R ; Varesco, L ; Gismondi, V ; Vellone, VG ; James, PA ; Janavicius, R ; Nikitina-Zake, L ; Nielsen, FC ; van Overeem Hansen, T ; Pejovic, T ; Borg, A ; Rantala, J ; Offit, K ; Montagna, M ; Nathanson, KL ; Domchek, SM ; Osorio, A ; Garcia, MJ ; Karlan, BY ; De Fazio, A ; Bowtell, D ; McGuffog, L ; Leslie, G ; Parsons, MT ; Doerk, T ; Speith, L-M ; dos Santos, ES ; da Costa, AABA ; Radice, P ; Peterlongo, P ; Papi, L ; Engel, C ; Hahnen, E ; Schmutzler, RK ; Wappenschmidt, B ; Easton, DF ; Tischkowitz, M ; Singer, CF ; Tan, YY ; Whittemore, AS ; Sieh, W ; Brenton, JD ; Yannoukakos, D ; Fostira, F ; Konstantopoulou, I ; Soukupova, J ; Vocka, M ; Chenevix-Trench, G ; Pharoah, PDP ; Antoniou, AC ; Goldgar, DE ; Spurdle, AB ; Michailidou, K ; Mourits, MJE ; Lesueur, F (SPRINGERNATURE, 2023-06-29)

BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)

Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmana, J ; Bandera, EV ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, NV ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dork, T ; du Bois, A ; Durst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Hogdall, E ; Hogdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Lubinski, J ; Mai, PL ; Manoukian, S ; Marks, JR ; Matsuno, RK ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, OI ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamarina, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; Terry, MB ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Van Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, JM ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 2022-05)
Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmana, J ; Bandera, E ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, N ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dork, T ; du Bois, A ; Durst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, R ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; Group, OS ; AOCSGroup, ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Hogdall, E ; Hogdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Mai, PL ; Manoukian, S ; Marks, JR ; KimMatsuno, R ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, O ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamarina, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; BethTerry, M ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 2022-03)

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Rebbeck, TR ; Friebel, TM ; Friedman, E ; Hamann, U ; Huo, D ; Kwong, A ; Olah, E ; Olopade, OI ; Solano, AR ; Teo, S-H ; Thomassen, M ; Weitzel, JN ; Chan, TL ; Couch, FJ ; Goldgar, DE ; Kruse, TA ; Palmero, EI ; Park, SK ; Torres, D ; van Rensburg, EJ ; McGuffog, L ; Parsons, MT ; Leslie, G ; Aalfs, CM ; Abugattas, J ; Adlard, J ; Agata, S ; Aittomaki, K ; Andrews, L ; Andrulis, IL ; Arason, A ; Arnold, N ; Arun, BK ; Asseryanis, E ; Auerbach, L ; Azzollini, J ; Balmana, J ; Barile, M ; Barkardottir, RB ; Barrowdale, D ; Benitez, J ; Berger, A ; Berger, R ; Blanco, AM ; Blazer, KR ; Blok, MJ ; Bonadona, V ; Bonanni, B ; Bradbury, AR ; Brewer, C ; Buecher, B ; Buys, SS ; Caldes, T ; Caliebe, A ; Caligo, MA ; Campbell, I ; Caputo, SM ; Chiquette, J ; Chung, WK ; Claes, KBM ; Collee, JM ; Cook, J ; Davidson, R ; de la Hoya, M ; De Leeneer, K ; de Pauw, A ; Delnatte, C ; Diez, O ; Ding, YC ; Ditsch, N ; Domchek, S ; Dorfling, CM ; Velazquez, C ; Dworniczak, B ; Eason, J ; Easton, DF ; Eeles, R ; Ehrencrona, H ; Ejlertsen, B ; Engel, C ; Engert, S ; Evans, DG ; Faivre, L ; Feliubadalo, L ; Ferrer, SF ; Foretova, L ; Fowler, J ; Frost, D ; Galvao, HCR ; Ganz, PA ; Garber, J ; Gauthier-Villars, M ; Gehrig, A ; Gerdes, A-M ; Gesta, P ; Giannini, G ; Giraud, S ; Glendon, G ; Godwin, AK ; Greene, MH ; Gronwald, J ; Gutierrez-Barrera, A ; Hahnen, E ; Hauke, J ; Henderson, A ; Hentschel, J ; Hogervorst, FBL ; Honisch, E ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Izquierdo, A ; Jakubowska, A ; James, P ; Janavicius, R ; Jensen, UB ; John, EM ; Vijai, J ; Kaczmarek, K ; Karlan, BY ; Kast, K ; Kim, S-W ; Konstantopoulou, I ; Korach, J ; Laitman, Y ; Lasa, A ; Lasset, C ; Lazaro, C ; Lee, A ; Lee, MH ; Lester, J ; Lesueur, F ; Liljegren, A ; Lindor, NM ; Longy, M ; Loud, JT ; Lu, KH ; Lubinski, J ; Machackova, E ; Manoukian, S ; Mari, V ; Martinez-Bouzas, C ; Matrai, Z ; Mebirouk, N ; Meijers-Heijboer, HEJ ; Meindl, A ; Mensenkamp, AR ; Mickys, U ; Miller, A ; Montagna, M ; Moysich, KB ; Mulligan, AM ; Musinsky, J ; Neuhausen, SL ; Nevanlinna, H ; Ngeow, J ; Nguyen, HP ; Niederacher, D ; Nielsen, HR ; Nielsen, FC ; Nussbaum, RL ; Offit, K ; Ofverholm, A ; Ong, K-R ; Osorio, A ; Papi, L ; Papp, J ; Pasini, B ; Pedersen, IS ; Peixoto, A ; Peruga, N ; Peterlongo, P ; Pohl, E ; Pradhan, N ; Prajzendanc, K ; Prieur, F ; Pujol, P ; Radice, P ; Ramus, SJ ; Rantala, J ; Rashid, MU ; Rhiem, K ; Robson, M ; Rodriguez, GC ; Rogers, MT ; Rudaitis, V ; Schmidt, AY ; Schmutzler, RK ; Senter, L ; Shah, PD ; Sharma, P ; Side, LE ; Simard, J ; Singer, CF ; Skytte, A-B ; Slavin, TP ; Snape, K ; Sobol, H ; Southey, M ; Steele, L ; Steinemann, D ; Sukiennicki, G ; Sutter, C ; Szabo, CI ; Tan, YY ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomas, A ; Thull, DL ; Tischkowitz, M ; Tognazzo, S ; Toland, AE ; Topka, S ; Trainer, AH ; Tung, N ; van Asperen, CJ ; van der Hout, AH ; van der Kolk, LE ; van der Luijt, RB ; Van Heetvelde, M ; Varesco, L ; Varon-Mateeva, R ; Vega, A ; Villarreal-Garza, C ; von Wachenfeldt, A ; Walker, L ; Wang-Gohrke, S ; Wappenschmidt, B ; Weber, BHF ; Yannoukakos, D ; Yoon, S-Y ; Zanzottera, C ; Zidan, J ; Zorn, KK ; Selkirk, CGH ; Hulick, PJ ; Chenevix-Trench, G ; Spurdle, AB ; Antoniou, AC ; Nathanson, KL (WILEY-HINDAWI, 2018-05)

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Zhan, H ; Ahearn, TU ; Lecarpentier, J ; Barnes, D ; Beesley, J ; Qi, G ; Jiang, X ; O'Mara, TA ; Zhao, N ; Bolla, MK ; Dunning, AM ; Dennis, J ; Wang, Q ; Abu Ful, Z ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Arun, BK ; Auer, PL ; Azzollini, J ; Barrowdale, D ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, A ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bonanni, B ; Bondavalli, D ; Borg, A ; Brauch, H ; Brenner, H ; Briceno, I ; Broeks, A ; Brucker, SY ; Bruening, T ; Burwinkel, B ; Buys, SS ; Byers, H ; Caldes, T ; Caligo, MA ; Calvello, M ; Campa, D ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiaens, M ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Diez, O ; Domchek, SM ; Doerk, T ; Dwek, M ; Eccles, DM ; Ekici, AB ; Evans, DG ; Fasching, PA ; Figueroa, J ; Foretova, L ; Fostira, F ; Friedman, E ; Frost, D ; Gago-Dominguez, M ; Gapstur, SM ; Garber, J ; Garcia-Saenz, JA ; Gaudet, MM ; Gayther, SA ; Giles, GG ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haeberle, L ; Hahnen, E ; Haiman, CA ; Hake, CR ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Hillemanns, P ; Hogervorst, FBL ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Huebner, H ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Jager, A ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Janni, W ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kapoor, PM ; Karlan, BY ; Keeman, R ; Khan, S ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Konstantopoulou, I ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Laenkholm, A-V ; Lambrechts, D ; Larsson, SC ; Laurent-Puig, P ; Lazaro, C ; Lazarova, E ; Lejbkowicz, F ; Leslie, G ; Lesueur, F ; Lindblom, A ; Lissowska, J ; Lo, W-Y ; Loud, JT ; Lubinski, J ; Lukomska, A ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Matricardi, L ; McGuffog, L ; McLean, C ; Mebirouk, N ; Meindl, A ; Menon, U ; Miller, A ; Mingazheva, E ; Montagna, M ; Mulligan, AM ; Mulot, C ; Muranen, TA ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Newman, WG ; Nielsens, FC ; Nikitina-Zake, L ; Nodora, J ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Orr, N ; Papi, L ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Peissel, B ; Peixoto, A ; Peshkin, B ; Peterlongo, P ; Peto, J ; Phillips, K-A ; Piedmonte, M ; Plaseska-Karanfilska, D ; Prajzendanc, K ; Prentice, R ; Prokofyeva, D ; Rack, B ; Radice, P ; Ramus, SJ ; Rantala, J ; Rashid, MU ; Rennert, G ; Rennert, HS ; Risch, HA ; Romero, A ; Rookus, MA ; Ruebner, M ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Scheuner, MT ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schoettker, B ; Schuermann, P ; Senter, L ; Sharma, P ; Sherman, ME ; Shu, X-O ; Singer, CF ; Smichkoska, S ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Stone, J ; Stoppa-Lyonnet, D ; Swerdlow, AJ ; Szabo, C ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, M ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Troester, MA ; Truong, T ; Tung, N ; Untch, M ; Vachon, CM ; van den Ouweland, AMW ; van der Kolk, LE ; van Veen, EM ; vanRensburg, EJ ; Vega, A ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wildiers, H ; Winqvist, R ; Wolk, A ; Yang, XR ; Yannoukakos, D ; Zheng, W ; Zorn, KK ; Milne, RL ; Kraft, P ; Simard, J ; Pharoah, PDP ; Michailidou, K ; Antoniou, AC ; Schmidt, MK ; Chenevix-Trench, G ; Easton, DF ; Chatterjee, N ; Garcia-Closas, M (NATURE RESEARCH, 2020-06)

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Kelemen, LE ; Earp, M ; Fridley, BL ; Chenevix-Trench, G ; Fasching, PA ; Beckmann, MW ; Ekici, AB ; Hein, A ; Lambrechts, D ; Lambrechts, S ; Van Nieuwenhuysen, E ; Vergote, I ; Rossing, MA ; Doherty, JA ; Chang-Claude, J ; Behrens, S ; Moysich, KB ; Cannioto, R ; Lele, S ; Odunsi, K ; Goodman, MT ; Shvetsov, YB ; Thompson, PJ ; Wilkens, LR ; Doerk, T ; Antonenkova, N ; Bogdanova, N ; Hillemanns, P ; Runnebaum, IB ; du Bois, A ; Harter, P ; Heitz, F ; Schwaab, I ; Butzow, R ; Pelttari, LM ; Nevanlinna, H ; Modugno, F ; Edwards, RP ; Kelley, JL ; Ness, RB ; Karlan, BY ; Lester, J ; Orsulic, S ; Walsh, C ; Kjaer, SK ; Jensen, A ; Cunningham, JM ; Vierkant, RA ; Giles, GG ; Bruinsma, F ; Southey, MC ; Hildebrandt, MAT ; Liang, D ; Lu, K ; Wu, X ; Sellers, TA ; Levine, DA ; Schildkraut, JM ; Iversen, ES ; Terry, KL ; Cramer, DW ; Tworoger, SS ; Poole, EM ; Bandera, EV ; Olson, SH ; Orlow, I ; Thomsen, LCV ; Bjorge, L ; Krakstad, C ; Tangen, IL ; Kiemeney, LA ; Aben, KKH ; Massuger, LFAG ; van Altena, AM ; Pejovic, T ; Bean, Y ; Kellar, M ; Cook, LS ; Le, ND ; Brooks-Wilson, A ; Gronwald, J ; Cybulski, C ; Jakubowska, A ; Lubinski, J ; Wentzensen, N ; Brinton, LA ; Lissowska, J ; Hogdall, E ; Engelholm, SA ; Hogdall, C ; Lundvall, L ; Nedergaard, L ; Pharoah, PDP ; Dicks, E ; Song, H ; Tyrer, JP ; McNeish, I ; Siddiqui, N ; Carty, K ; Glasspool, R ; Paul, J ; Campbell, IG ; Eccles, D ; Whittemore, AS ; McGuire, V ; Rothstein, JH ; Sieh, W ; Narod, SA ; Phelan, CM ; McLaughlin, JR ; Risch, HA ; Anton-Culver, H ; Ziogas, A ; Menon, U ; Gayther, SA ; Gentry-Maharaj, A ; Ramus, SJ ; Wu, AH ; Pearce, CL ; Lee, AW ; Pike, MC ; Kupryjanczyk, J ; Podgorska, A ; Plisiecka-Halasa, J ; Sawicki, W ; Goode, EL ; Berchuck, A (MDPI, 2018-09)

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Identification of six new susceptibility loci for invasive epithelial ovarian cancer

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, TVO ; Jonson, L ; Gerdes, A-M ; 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 ; Aittomaeki, K ; Nevanlinna, H ; Collee, JM ; Rookus, MA ; Oosterwijk, JC ; Tihomirova, L ; Tung, N ; Hamann, U ; Isaccs, C ; Tischkowitz, M ; Imyanitov, EN ; Caligo, MA ; Campbell, IG ; Hogervorst, FBL ; Olah, E ; Diez, O ; Blanco, I ; Brunet, J ; Lazaroso, C ; Angel Pujana, M ; 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, M-K ; 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 ; Duerst, M ; Hillemanns, P ; Doerk, 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, MAN ; Teo, S-H ; Woo, Y-L ; Fridley, BL ; Goode, EL ; Cunningham, JM ; Vierkant, RA ; Bruinsma, F ; Giles, GG ; Liang, D ; Hildebrandt, MAT ; 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, KKH ; Kiemeney, LA ; Massuger, LFAG ; 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, B-T ; Zheng, W ; Shu, X-O ; Gao, Y-T ; Rosen, B ; Risch, HA ; McLaughlin, JR ; Narod, SA ; Monteiro, AN ; Chen, A ; Lin, H-Y ; Permuth-Wey, J ; Sellers, TA ; Tsai, Y-Y ; 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 ; Chenevix-Trench, G (NATURE PORTFOLIO, 2015-02)

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.
COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

Southey, MC ; Park, DJ ; Nguyen-Dumont, T ; Campbell, I ; Thompson, E ; Trainer, AH ; Chenevix-Trench, G ; Simard, J ; Dumont, M ; Soucy, P ; Thomassen, M ; Jonson, L ; Pedersen, IS ; Hansen, TVO ; Nevanlinna, H ; Khan, S ; Sinilnikova, O ; Mazoyer, S ; Lesueur, F ; Damiola, F ; Schmutzler, R ; Meindl, A ; Hahnen, E ; Dufault, MR ; Chan, TC ; Kwong, A ; Barkardottir, R ; Radice, P ; Peterlongo, P ; Devilee, P ; Hilbers, F ; Benitez, J ; Kvist, A ; Torngren, T ; Easton, D ; Hunter, D ; Lindstrom, S ; Kraft, P ; Zheng, W ; Gao, Y-T ; Long, J ; Ramus, S ; Feng, B-J ; Weitzel, RN ; Nathanson, K ; Offit, K ; Joseph, V ; Robson, M ; Schrader, K ; Wang, SM ; Kim, YC ; Lynch, H ; Snyder, C ; Tavtigian, S ; Neuhausen, S ; Couch, FJ ; Goldgar, DE (BMC, 2013)

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.
GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Pharoah, PDP ; Tsai, Y-Y ; Ramus, SJ ; Phelan, CM ; Goode, EL ; Lawrenson, K ; Buckley, M ; Fridley, BL ; Tyrer, JP ; Shen, H ; Weber, R ; Karevan, R ; Larson, MC ; Song, H ; Tessier, DC ; Bacot, F ; Vincent, D ; Cunningham, JM ; Dennis, J ; Dicks, E ; Aben, KK ; Anton-Culver, H ; Antonenkova, N ; Armasu, SM ; Baglietto, L ; Bandera, EV ; Beckmann, MW ; Birrer, MJ ; Bloom, G ; Bogdanova, N ; Brenton, JD ; Brinton, LA ; Brooks-Wilson, A ; Brown, R ; Butzow, R ; Campbell, I ; Carney, ME ; Carvalho, RS ; Chang-Claude, J ; Chen, YA ; Chen, Z ; Chow, W-H ; Cicek, MS ; Coetzee, G ; Cook, LS ; Cramer, DW ; Cybulski, C ; Dansonka-Mieszkowska, A ; Despierre, E ; Doherty, JA ; Doerk, T ; du Bois, A ; Duerst, M ; Eccles, D ; Edwards, R ; Ekici, AB ; Fasching, PA ; Fenstermacher, D ; Flanagan, J ; Gao, Y-T ; Garcia-Closas, M ; Gentry-Maharaj, A ; Giles, G ; Gjyshi, A ; Gore, M ; Gronwald, J ; Guo, Q ; Halle, MK ; Harter, P ; Hein, A ; Heitz, F ; Hillemanns, P ; Hoatlin, M ; Hogdall, E ; Hogdall, CK ; Hosono, S ; Jakubowska, A ; Jensen, A ; Kalli, KR ; Karlan, BY ; Kelemen, LE ; Kiemeney, LA ; Kjaer, SK ; Konecny, GE ; Krakstad, C ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, N ; Lee, J ; Leminen, A ; Lim, BK ; Lissowska, J ; Lubinski, J ; Lundvall, L ; Lurie, G ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; Menon, U ; Modugno, F ; Moysich, KB ; Nakanishi, T ; Narod, SA ; Ness, RB ; Nevanlinna, H ; Nickels, S ; Noushmehr, H ; Odunsi, K ; Olson, S ; Orlow, I ; Paul, J ; Pejovic, T ; Pelttari, LM ; Permuth-Wey, J ; Pike, MC ; Poole, EM ; Qu, X ; Risch, HA ; Rodriguez-Rodriguez, L ; Rossing, MA ; Rudolph, A ; Runnebaum, I ; Rzepecka, IK ; Salvesen, HB ; Schwaab, I ; Severi, G ; Shen, H ; Shridhar, V ; Shu, X-O ; Sieh, W ; Southey, MC ; Spellman, P ; Tajima, K ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Timorek, A ; Tworoger, SS ; van Altena, AM ; van den Berg, D ; Vergote, I ; Vierkant, RA ; Vitonis, AF ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wik, E ; Winterhoff, B ; Woo, YL ; Wu, AH ; Yang, HP ; Zheng, W ; Ziogas, A ; Zulkifli, F ; Goodman, MT ; Hall, P ; Easton, DF ; Pearce, CL ; Berchuck, A ; Chenevix-Trench, G ; Iversen, E ; Monteiro, ANA ; Gayther, SA ; Schildkraut, JM ; Sellers, TA (NATURE PUBLISHING GROUP, 2013-04)

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Permuth-Wey, J ; Lawrenson, K ; Shen, HC ; Velkova, A ; Tyrer, JP ; Chen, Z ; Lin, H-Y ; Chen, YA ; Tsai, Y-Y ; Qu, X ; Ramus, SJ ; Karevan, R ; Lee, J ; Lee, N ; Larson, MC ; Aben, KK ; Anton-Culver, H ; Antonenkova, N ; Antoniou, AC ; Armasu, SM ; Bacot, F ; Baglietto, L ; Bandera, EV ; Barnholtz-Sloan, J ; Beckmann, MW ; Birrer, MJ ; Bloom, G ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Brown, R ; Butzow, R ; Cai, Q ; Campbell, I ; Chang-Claude, J ; Chanock, S ; Chenevix-Trench, G ; Cheng, JQ ; Cicek, MS ; Coetzee, GA ; Cook, LS ; Couch, FJ ; Cramer, DW ; Cunningham, JM ; Dansonka-Mieszkowska, A ; Despierre, E ; Doherty, JA ; Doerk, T ; du Bois, A ; Duerst, M ; Easton, DF ; Eccles, D ; Edwards, R ; Ekici, AB ; Fasching, PA ; Fenstermacher, DA ; Flanagan, JM ; Garcia-Closas, M ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, RM ; Gonzalez-Bosquet, J ; Goodman, MT ; Gore, M ; Gorski, B ; Gronwald, J ; Hall, P ; Halle, MK ; Harter, P ; Heitz, F ; Hillemanns, P ; Hoatlin, M ; Hogdall, CK ; Hogdall, E ; Hosono, S ; Jakubowska, A ; Jensen, A ; Jim, H ; Kalli, KR ; Karlan, BY ; Kaye, SB ; Kelemen, LE ; Kiemeney, LA ; Kikkawa, F ; Konecny, GE ; Krakstad, C ; Kjaer, SK ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Lancaster, JM ; Le, ND ; Leminen, A ; Levine, DA ; Liang, D ; Lim, BK ; Lin, J ; Lissowska, J ; Lu, KH ; Lubinski, J ; Lurie, G ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; Menon, U ; Modugno, F ; Moysich, KB ; Nakanishi, T ; Narod, SA ; Nedergaard, L ; Ness, RB ; Nevanlinna, H ; Nickels, S ; Noushmehr, H ; Odunsi, K ; Olson, SH ; Orlow, I ; Paul, J ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Pike, MC ; Poole, EM ; Raska, P ; Renner, SP ; Risch, HA ; Rodriguez-Rodriguez, L ; Rossing, MA ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schwaab, I ; Severi, G ; Shridhar, V ; Shu, X-O ; Shvetsov, YB ; Sieh, W ; Song, H ; Southey, MC ; Spiewankiewicz, B ; Stram, D ; Sutphen, R ; Teo, S-H ; Terry, KL ; Tessier, DC ; Thompson, PJ ; Tworoger, SS ; van Altena, AM ; Vergote, I ; Vierkant, RA ; Vincent, D ; Vitonis, AF ; Wang-Gohrke, S ; Weber, RP ; Wentzensen, N ; Whittemore, AS ; Wik, E ; Wilkens, LR ; Winterhoff, B ; Woo, YL ; Wu, AH ; Xiang, Y-B ; Yang, HP ; Zheng, W ; Ziogas, A ; Zulkifli, F ; Phelan, CM ; Iversen, E ; Schildkraut, JM ; Berchuck, A ; Fridley, BL ; Goode, EL ; Pharoah, PDP ; Monteiro, ANA ; Sellers, TA ; Gayther, SA (NATURE RESEARCH, 2013-03)

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

Sir Peter MacCallum Department of Oncology - Research Publications

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