Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

Barnes, DR; Tyrer, JP; Dennis, J; Leslie, G; Bolla, MK; Lush, M; Aeilts, AM; Aittom&#228;ki, K; Andrieu, N; Andrulis, IL; Anton-Culver, H; Arason, A; Arun, BK; Balma&#241;a, J; Bandera, EV; Barkardottir, RB; Berger, LPV; Berrington de Gonzalez, A; Berthet, P; Białkowska, K; Bj&#248;rge, L; Blanco, AM; Blok, MJ; Bobolis, KA; Bogdanova, NV; Brenton, JD; Butz, H; Buys, SS; Caligo, MA; Campbell, I; Castillo, C; Claes, KBM; Colonna, SV; Cook, LS; Daly, MB; Dansonka-Mieszkowska, A; de la Hoya, M; DeFazio, A; DePersia, A; Ding, YC; Doherty, JA; Domchek, SM; D&#246;rk, T; Einbeigi, Z; Engel, C; Evans, DG; Foretova, L; Fortner, RT; Fostira, F; Foti, MC; Friedman, E; Frone, MN; Ganz, PA; Gentry-Maharaj, A; Glendon, G; Godwin, AK; Gonz&#225;lez-Neira, A; Greene, MH; Gronwald, J; Guerrieri-Gonzaga, A; Hamann, U; Hansen, TVO; Harris, HR; Hauke, J; Heitz, F; Hogervorst, FBL; Hooning, MJ; Hopper, JL; Huff, CD; Huntsman, DG; Imyanitov, EN; Izatt, L; Jakubowska, A; James, PA; Janavicius, R; John, EM; Kar, S; Karlan, BY; Kennedy, CJ; Kiemeney, Lalm; Konstantopoulou, I; Kupryjanczyk, J; Laitman, Y; Lavie, O; Lawrenson, K; Lester, J; Lesueur, F; Lopez-Pleguezuelos, C; Mai, PL; Manoukian, S; May, T; McNeish, IA; Menon, U; Milne, RL; Modugno, F; Mongiovi, JM; Montagna, M; Moysich, KB; Neuhausen, SL; Nielsen, FC; Nogu&#232;s, C; Ol&#225;h, E; Olopade, OI; Osorio, A; Papi, L; Pathak, H; Pearce, CL; Pedersen, IS; Peixoto, A; Pejovic, T; Peng, PC; Peshkin, BN; Peterlongo, P; Powell, CB; Prokofyeva, D; Pujana, MA; Radice, P; Rashid, MU; Rennert, G; Richenberg, G; Sandler, DP; Sasamoto, N; Setiawan, VW; Sharma, P; Sieh, W; Singer, CF; Snape, K; Sokolenko, AP; Soucy, P; Southey, MC; Stoppa-Lyonnet, D; Sutphen, R; Sutter, C; Tan, YY; Teixeira, MR; Terry, KL; Thomsen, LCV; Tischkowitz, M; Toland, AE; Van Gorp, T; Vega, A; Velez Edwards, DR; Webb, PM; Weitzel, JN; Wentzensen, N; Whittemore, AS; Winham, SJ; Wu, AH; Yadav, S; Yu, Y; Ziogas, A; Berchuck, A; Couch, FJ; Goode, EL; Goodman, MT; Monteiro, AN; Offit, K; Ramus, SJ; Risch, HA; Schildkraut, JM; Thomassen, M; Simard, J; Easton, DF; Jones, MR; Chenevix-Trench, G; Gayther, SA; Antoniou, AC; Pharoah, PDP

Author(s): Barnes, DR; Tyrer, JP; Dennis, J; Leslie, G; Bolla, MK; Lush, M; Aeilts, AM; Aittomäki, K; Andrieu, N; Andrulis, IL; Anton-Culver, H; Arason, A; Arun, BK; Balmaña, J; Bandera, EV; Barkardottir, RB; Berger, LPV; Berrington de Gonzalez, A; Berthet, P; Białkowska, K; Bjørge, L; Blanco, AM; Blok, MJ; Bobolis, KA; Bogdanova, NV; Brenton, JD; Butz, H; Buys, SS; Caligo, MA; Campbell, I; Castillo, C; Claes, KBM; Colonna, SV; Cook, LS; Daly, MB; Dansonka-Mieszkowska, A; de la Hoya, M; DeFazio, A; DePersia, A; Ding, YC; Doherty, JA; Domchek, SM; Dörk, T; Einbeigi, Z; Engel, C; Evans, DG; Foretova, L; Fortner, RT; Fostira, F; Foti, MC; Friedman, E; Frone, MN; Ganz, PA; Gentry-Maharaj, A; Glendon, G; Godwin, AK; González-Neira, A; Greene, MH; Gronwald, J; Guerrieri-Gonzaga, A; Hamann, U; Hansen, TVO; Harris, HR; Hauke, J; Heitz, F; Hogervorst, FBL; Hooning, MJ; Hopper, JL; Huff, CD; Huntsman, DG; Imyanitov, EN; Izatt, L; Jakubowska, A; James, PA; Janavicius, R; John, EM; Kar, S; Karlan, BY; Kennedy, CJ; Kiemeney, Lalm; Konstantopoulou, I; Kupryjanczyk, J; Laitman, Y; Lavie, O; Lawrenson, K; Lester, J; Lesueur, F; Lopez-Pleguezuelos, C; Mai, PL; Manoukian, S; May, T; McNeish, IA; Menon, U; Milne, RL; Modugno, F; Mongiovi, JM; Montagna, M; Moysich, KB; Neuhausen, SL; Nielsen, FC; Noguès, C; Oláh, E; Olopade, OI; Osorio, A; Papi, L; Pathak, H; Pearce, CL; Pedersen, IS; Peixoto, A; Pejovic, T; Peng, PC; Peshkin, BN; Peterlongo, P; Powell, CB; Prokofyeva, D; Pujana, MA; Radice, P; Rashid, MU; Rennert, G; Richenberg, G; Sandler, DP; Sasamoto, N; Setiawan, VW; Sharma, P; Sieh, W; Singer, CF; Snape, K; Sokolenko, AP; Soucy, P; Southey, MC; Stoppa-Lyonnet, D; Sutphen, R; Sutter, C; Tan, YY; Teixeira, MR; Terry, KL; Thomsen, LCV; Tischkowitz, M; Toland, AE; Van Gorp, T; Vega, A; Velez Edwards, DR; Webb, PM; Weitzel, JN; Wentzensen, N; Whittemore, AS; Winham, SJ; Wu, AH; Yadav, S; Yu, Y; Ziogas, A; Berchuck, A; Couch, FJ; Goode, EL; Goodman, MT; Monteiro, AN; Offit, K; Ramus, SJ; Risch, HA; Schildkraut, JM; Thomassen, M; Simard, J; Easton, DF; Jones, MR; Chenevix-Trench, G; Gayther, SA; Antoniou, AC; Pharoah, PDP;
Details: Publication Year 2025-11-20,Volume 10,Issue #1,Page 73
Journal Title: NPJ Genomic Medicine
Publication Type: Research article
Abstract: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3'-UTR SNP rs78378222-T's association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28-1.62, P = 1.76 × 10(-9)). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37-1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date - demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.
Publisher: Springer Nature
Department(s): Laboratory Research; Familial Cancer Centre
Publisher's Version: https://doi.org/10.1038/s41525-025-00529-w
Open Access at Publisher's Site: https://doi.org/10.1038/s41525-025-00529-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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