Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

Rebbeck TR; Mitra N; Wan F; Sinilnikova OM; Healey S; McGuffog L; Mazoyer S; Chenevix Trench G; Easton DF; Antoniou AC; Nathanson KL; CIMBA Consortium; Laitman Y; Kushnir A; Paluch Shimon S; Berger R; Zidan J; Friedman E; Ehrencrona H; Stenmark Askmalm M; Einbeigi Z; Loman N; Harbst K; Rantala J; Melin B; Huo D; Olopade OI; Seldon J; Ganz PA; Nussbaum RL; Chan SB; Odunsi K; Gayther SA; Domchek SM; Arun BK; Lu KH; Mitchell G; Karlan BY; Walsh C; Lester J; Godwin AK; Pathak H; Ross E; Daly MB; Whittemore AS; John EM; Miron A; Terry MB; Chung WK; Goldgar DE; Buys SS; Janavicius R; Tihomirova L; Tung N; Dorfling CM; van Rensburg EJ; Steele L; Neuhausen SL; Ding YC; Ejlertsen B; Gerdes AM; Hansen Tv; Ramón y. Cajal T; Osorio A; Benitez J; Godino J; Tejada MI; Duran M; Weitzel JN; Bobolis KA; Sand SR; Fontaine A; Savarese A; PASINI, Barbara; Peissel B; Bonanni B; Zaffaroni D; Vignolo Lutati F; Scuvera G; Giannini G; Bernard L; Genuardi M; Radice P; Dolcetti R; Manoukian S; Pensotti V; Gismondi V; Yannoukakos D; Fostira F; Garber J; Torres D; Rashid MU; Hamann U; Peock S; Frost D; Platte R; Evans DG; Eeles R; Davidson R; Eccles D; Cole T; Cook J; Brewer C; Hodgson S; Morrison PJ; Walker L; Porteous ME; Kennedy MJ; Izatt L; Adlard J; Donaldson A; Ellis S; Sharma P; Schmutzler RK; Wappenschmidt B; Becker A; Rhiem K; Hahnen E; Engel C; Meindl A; Engert S; Ditsch N; Arnold N; Plendl HJ; Mundhenke C; Niederacher D; Fleisch M; Sutter C; Bartram CR; Dikow N; Wang Gohrke S; Gadzicki D; Steinemann D; Kast K; Beer M; Varon Mateeva R; Gehrig A; Weber BH; Stoppa Lyonnet D; Sinilnikova OM; Mazoyer S; Houdayer C; Belotti M; Gauthier Villars M; Damiola F; Boutry Kryza N; Lasset C; Sobol H; Peyrat JP; Muller D; Fricker JP; Collonge Rame MA; Mortemousque I; Nogues C; Rouleau E; Isaacs C; De Paepe A; Poppe B; Claes K; De Leeneer K; Piedmonte M; Rodriguez G; Wakely K; Boggess J; Blank SV; Basil J; Azodi M; Phillips KA; Caldes T; de la Hoya M; Romero A; Nevanlinna H; Aittomäki K; van der Hout AH; Hogervorst FB; Verhoef S; Collée JM; Seynaeve C; Oosterwijk JC; Gille JJ; Wijnen JT; Gómez Garcia EB; Kets CM; Ausems MG; Aalfs CM; Devilee P; Mensenkamp AR; Kwong A; Olah E; Papp J; Diez O; Lazaro C; Darder E; Blanco I; Salinas M; Jakubowska A; Lubinski J; Gronwald J; Jaworska Bieniek K; Durda K; Sukiennicki G; Huzarski T; Byrski T; Cybulski C; Toloczko Grabarek A; Złowocka Perłowska E; Menkiszak J; Arason A; Barkardottir RB; Simard J; Laframboise R; Montagna M; Agata S; Alducci E; Peixoto A; Teixeira MR; Spurdle AB; Lee MH; Park SK; Kim SW; Friebel TM; Couch FJ; Lindor NM; Pankratz VS; Guidugli L; Wang X; Tischkowitz M; Foretova L; Vijai J; Offit K; Robson M; Rau Murthy R; Kauff N; Fink Retter A; Singer CF; Rappaport C; Gschwantler Kaulich D; Pfeiler G; Tea MK; Berger A; Greene MH; Mai PL; Imyanitov EN; Toland AE; Senter L; Bojesen A; Pedersen IS; Skytte AB; Sunde L; Thomassen M; Moeller ST; Kruse TA; Jensen UB; Caligo MA; Aretini P; Teo SH; Selkirk CG; Hulick PJ; Andrulis I.

doi:10.1001/jama.2014.5985

IMPORTANCE—Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE—To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS—Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES—Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES—Breast and ovarian cancer risks.