Sir Peter MacCallum Department of Oncology - Research Publications

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Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

DeVries, AA ; Dennis, J ; Tyrer, JP ; Peng, P-C ; Coetzee, SG ; Reyes, AL ; Plummer, JT ; Davis, BD ; Chen, SS ; Dezem, FS ; Aben, KKH ; Anton-Culver, H ; Antonenkova, NN ; Beckmann, MW ; Beeghly-Fadiel, A ; Berchuck, A ; Bogdanova, N ; Bogdanova-Markov, N ; Brenton, JD ; Butzow, R ; Campbell, I ; Chang-Claude, J ; Chenevix-Trench, G ; Cook, LS ; DeFazio, A ; Doherty, JA ; Dork, T ; Eccles, DM ; Eliassen, AH ; Fasching, PA ; Fortner, RT ; Giles, GG ; Goode, EL ; Goodman, MT ; Gronwald, J ; Hakansson, N ; Hildebrandt, MAT ; Huff, C ; Huntsman, DG ; Jensen, A ; Kar, S ; Karlan, BY ; Khusnutdinova, EK ; Kiemeney, LA ; Kjaer, SK ; Kupryjanczyk, J ; Labrie, M ; Lambrechts, D ; Le, ND ; Lubinski, J ; May, T ; Menon, U ; Milne, RL ; Modugno, F ; Monteiro, AN ; Moysich, KB ; Odunsi, K ; Olsson, H ; Pearce, CL ; Pejovic, T ; Ramus, SJ ; Riboli, E ; Riggan, MJ ; Romieu, I ; Sandler, DP ; Schildkraut, JM ; Setiawan, VW ; Sieh, W ; Song, H ; Sutphen, R ; Terry, KL ; Thompson, PJ ; Titus, L ; Tworoger, SS ; Van Nieuwenhuysen, E ; Edwards, DV ; Webb, PM ; Wentzensen, N ; Whittemore, AS ; Wolk, A ; Wu, AH ; Ziogas, A ; Freedman, ML ; Lawrenson, K ; Pharoah, PDP ; Easton, DF ; Gayther, SA ; Jones, MR (OXFORD UNIV PRESS INC, 2022-11)

BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
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.
Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Ahearn, TU ; Zhang, H ; Michailidou, K ; Milne, RL ; Bolla, MK ; Dennis, J ; Dunning, AM ; Lush, M ; Wang, Q ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Auer, PL ; Augustinsson, A ; Baten, A ; Becher, H ; Behrens, S ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dwek, M ; Eccles, DM ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Jakimovska, M ; Jakubowska, A ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kauppila, S ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kubelka-Sabit, K ; Kurian, AW ; Kyriacou, K ; Lambrechts, D ; Lee, DG ; Lindblom, A ; Linet, M ; Lissowska, J ; Llaneza, A ; Lo, W-Y ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; McLean, C ; Meindl, A ; Menon, U ; Nevanlinna, H ; Newman, WG ; Nodora, J ; Offit, K ; Olsson, H ; Orr, N ; Park-Simon, T-W ; Patel, A ; Peto, J ; Pita, G ; Plaseska-Karanfilska, D ; Prentice, R ; Punie, K ; Pylkas, K ; Radice, P ; Rennert, G ; Romero, A ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Schoemaker, MJ ; Schottker, B ; Sherman, ME ; Shu, X-O ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teras, LR ; Terry, MB ; Torres, D ; Troester, MA ; Vachon, CM ; van Deurzen, CHM ; van Veen, EM ; Wagner, P ; Weinberg, CR ; Wendt, C ; Wesseling, J ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Couch, FJ ; Simard, J ; Kraft, P ; Easton, DF ; Pharoah, PDP ; Schmidt, MK ; Garcia-Closas, M ; Chatterjee, N (BMC, 2022-01-04)

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Rare germline copy number variants (CNVs) and breast cancer risk

Dennis, J ; Tyrer, JP ; Walker, LC ; Michailidou, K ; Dorling, L ; Bolla, MK ; Wang, Q ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Freeman, LEB ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brenner, H ; Castelao, JE ; Chang-Claude, J ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Devilee, P ; Dork, T ; Dossus, L ; Eliassen, AH ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Fletcher, O ; Flyger, H ; Fritschi, L ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Closas, M ; Giles, GG ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hall, P ; Hollestelle, A ; Hoppe, R ; Hopper, JL ; Howell, A ; Jager, A ; Jakubowska, A ; John, EM ; Johnson, N ; Jones, ME ; Jung, A ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kubelka-Sabit, K ; Kurian, AW ; Lacey, J ; Lambrechts, D ; Larson, NL ; Linet, M ; Ogrodniczak, A ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Mavroudis, D ; Milne, RL ; Muranen, TA ; Murphy, RA ; Nevanlinna, H ; Olson, JE ; Olsson, H ; Park-Simon, T-W ; Perou, CM ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Shibli, R ; Smeets, A ; Soucy, P ; Southey, MC ; Swerdlow, AJ ; Tamimi, RM ; Taylor, JA ; Teras, LR ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; Wendt, C ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Ziogas, A ; Simard, J ; Dunning, AM ; Pharoah, PDP ; Easton, DF (NATURE PORTFOLIO, 2022-01-18)

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Park, HA ; Neumeyer, S ; Michailidou, K ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baten, A ; Freeman, LEB ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brauch, H ; Brenner, H ; Brucker, SY ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dos-Santos-Silva, I ; Dwek, M ; Eccles, DM ; Eliassen, AH ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Flyger, H ; Fritschi, L ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Grip, M ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Han, S ; Harkness, EF ; Hart, SN ; He, W ; Heemskerk-Gerritsen, BAM ; Hopper, JL ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Jung, A ; Kaaks, R ; Kapoor, PM ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Kurian, AW ; Lacey, J ; Lambrechts, D ; LeMarchand, L ; Lo, W-Y ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; ElenaMartinez, M ; Mavroudis, D ; Meindl, A ; Menon, U ; Milne, RL ; Muranen, TA ; Nevanlinna, H ; Newman, WG ; Nordestgaard, BG ; Offit, K ; Olshan, AF ; Olsson, H ; Park-Simon, T-W ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Presneau, N ; Radice, P ; Rennert, G ; Rennert, HS ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Schoemaker, MJ ; Schwentner, L ; Scott, C ; Shah, M ; Shu, X-O ; Simard, J ; Smeets, A ; Southey, MC ; Spinelli, JJ ; Stevens, V ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Vijai, J ; Wang, S ; Wendt, C ; Winqvist, R ; Wolk, A ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Zheng, W ; Kraft, P ; Chang-Claude, J (SPRINGERNATURE, 2021-10-12)

BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Johnson, N ; Maguire, S ; Morra, A ; Kapoor, PM ; Tomczyk, K ; Jones, ME ; Schoemaker, MJ ; Gilham, C ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baynes, C ; Freeman, LEB ; Beckmann, MW ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Boeckx, B ; Bogdanova, NV ; Bojesen, SE ; Brauch, H ; Brenner, H ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Doerk, T ; Eliassen, AH ; Engel, C ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Flyger, H ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Closas, M ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hart, SN ; Hooning, MJ ; Hopper, JL ; Howell, A ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Le Marchand, L ; Linet, M ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Martens, JWM ; Mavroudis, D ; Mayes, R ; Meindl, A ; Milne, RL ; Neuhausen, SL ; Nevanlinna, H ; Newman, WG ; Nielsen, SF ; Nordestgaard, BG ; Obi, N ; Olshan, AF ; Olson, JE ; Olsson, H ; Orban, E ; Park-Simon, T-W ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Rennert, HS ; Ruddy, KJ ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Scott, C ; Shu, X-O ; Simard, J ; Smichkoska, S ; Sohn, C ; Southey, MC ; Spinelli, JJ ; Stone, J ; Tamimi, RM ; Taylor, JA ; Tollenaar, RAEM ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Wang, SS ; Weinberg, CR ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Zheng, W ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Howie, AF ; Peto, J ; dos-Santos-Silva, I ; Swerdlow, AJ ; Chang-Claude, J ; Schmidt, MK ; Orr, N ; Fletcher, O (SPRINGERNATURE, 2021-02-16)

BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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.
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.

Sir Peter MacCallum Department of Oncology - Research Publications

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