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; Q, Li; 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, Laura; Ottini, L; Fostira, F; Konstantopoulou, I; Garber, J; Frost, D; Perkins, J; Platte, R; Ellis, S; Embrace,; Godwin, Ak; Schmutzler, Rk; Meindl, A; Engel, C; Sutter, C; Sinilnikova, Om; GEMO Study Collaborators,; 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; Breast Cancer Family Registry,; Tihomirova, L; Tung, N; Hamann, U; Isaccs, C; Tischkowitz, M; Imyanitov, En; Caligo, Ma; Campbell, Ig; Hogervorst, Fb; Hebon,; 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; Investigators, Kconfab; 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; Kh, Lu; Karlan, By; Walsh, C; Lester, J; Australian Cancer Study,; Australian Ovarian Cancer Study Group,; 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; X, Wu; 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; Nd, Le; 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; Bt, Ji; 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; Ah, Wu; 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; Consortium of Investigators of Modifiers of BRCA1,; B. R. C. A. 2.,

doi:10.1038/ng.3185

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.

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 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; EMBRACE.; Godwin AK; Schmutzler RK; Meindl A; Engel C; Sutter C; Sinilnikova OM; GEMO Study Collaborators.; 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; Breast Cancer Family Registry.; Tihomirova L; Tung N; Hamann U; Isaccs C; Tischkowitz M; Imyanitov EN; Caligo MA; Campbell IG; Hogervorst FB; HEBON.; 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; KConFab Investigators.; 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; Australian Cancer Study (Ovarian Cancer Investigators).; Australian Ovarian Cancer Study Group.; 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; Chenevix-Trench G; Consortium of Investigators of Modifiers of BRCA1 and BRCA2.. - In: NATURE GENETICS. - ISSN 1546-1718. - STAMPA. - 47:(2015), pp. 164-171. [10.1038/ng.3185]