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Title: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
Authors: Coignard J,  Lush M,  Beesley J,  O'Mara TA,  Dennis J,  Tyrer JP,  Barnes DR,  McGuffog L,  Leslie G,  Bolla MK,  Adank MA,  Agata S,  Ahearn T,  Aittomäki K,  Andrulis IL,  Anton-Culver H,  Arndt V,  Arnold N,  Aronson KJ,  Arun BK,  Augustinsson A,  Azzollini J,  Barrowdale D,  Baynes C,  Becher H,  Bermisheva M,  Bernstein L,  Białkowska K,  Blomqvist C,  Bojesen SE,  Bonanni B,  Borg A,  Brauch H,  Brenner H,  Burwinkel B,  Buys SS,  Caldés T,  Caligo MA,  Campa D,  Carter BD,  Castelao JE,  Chang-Claude J,  Chanock SJ,  Chung WK,  Claes KBM,  Clarke CL,  GEMO Study Collaborators,  EMBRACE Collaborators,  Collée JM,  Conroy DM,  Czene K,  Daly MB,  Devilee P,  Diez O,  Ding YC,  Domchek SM,  Dörk T,  Dos-Santos-Silva I,  Dunning AM,  Dwek M,  Eccles DM,  Eliassen AH,  Engel C,  Eriksson M,  Evans DG,  Fasching PA,  Flyger H,  Fostira F,  Friedman E,  Fritschi L,  Frost D,  Gago-Dominguez M,  Gapstur SM,  Garber J,  Garcia-Barberan V,  García-Closas M,  García-Sáenz JA,  Gaudet MM,  Gayther SA,  Gehrig A,  Georgoulias V,  Giles GG,  Godwin AK,  Goldberg MS,  Goldgar DE,  González-Neira A,  Greene MH,  Guénel P,  Haeberle L,  Hahnen E,  Haiman CA,  Håkansson N,  Hall P,  Hamann U,  Harrington PA,  Hart SN,  He W,  Hogervorst FBL,  Hollestelle A,  Hopper JL,  Horcasitas DJ,  Hulick PJ,  Hunter DJ,  Imyanitov EN,  KConFab Investigators,  HEBON Investigators,  ABCTB Investigators,  Jager A,  Jakubowska A,  James PA,  Jensen UB,  John EM,  Jones ME,  Kaaks R,  Kapoor PM,  Karlan BY,  Keeman R,  Khusnutdinova E,  Kiiski JI,  Ko YD,  Kosma VM,  Kraft P,  Kurian AW,  Laitman Y,  Lambrechts D,  Le Marchand L,  Lester J,  Lesueur F,  Lindstrom T,  Lopez-Fernández A,  Loud JT,  Luccarini C,  Mannermaa A,  Manoukian S,  Margolin S,  Martens JWM,  Mebirouk N,  Meindl A,  Miller A,  Milne RL,  Montagna M,  Nathanson KL,  Neuhausen SL,  Nevanlinna H,  Nielsen FC,  O'Brien KM,  Olopade OI,  Olson JE,  Olsson H,  Osorio A,  Ottini L,  Park-Simon TW,  Parsons MT,  Pedersen IS,  Peshkin B,  Peterlongo P,  Peto J,  Pharoah PDP,  Phillips KA,  Polley EC,  Poppe B,  Presneau N,  Pujana MA,  Punie K,  Radice P,  Rantala J,  Rashid MU,  Rennert G,  Rennert HS,  Robson M,  Romero A,  Rossing M,  Saloustros E,  Sandler DP,  Santella R,  Scheuner MT,  Schmidt MK,  Schmidt G,  Scott C,  Sharma P,  Soucy P,  Southey MC,  Spinelli JJ,  Steinsnyder Z,  Stone J,  Stoppa-Lyonnet D,  Swerdlow A,  Tamimi RM,  Tapper WJ,  Taylor JA,  Terry MB,  Teulé A,  Thull DL,  Tischkowitz M,  Toland AE,  Torres D,  Trainer AH,  Truong T,  Tung N,  Vachon CM,  Vega A,  Vijai J,  Wang Q,  Wappenschmidt B,  Weinberg CR,  Weitzel JN,  Wendt C,  Wolk A,  Yadav S,  Yang XR,  Yannoukakos D,  Zheng W,  Ziogas A,  Zorn KK,  Park SK,  Thomassen M,  Offit K,  Schmutzler RK,  Couch FJ,  Simard J,  Chenevix-Trench G,  Easton DF,  Andrieu N,  Antoniou AC
Journal: Nat Commun
Date: 2021 Feb 17
Branches: CGB, CGR, OD, TDRP
PubMed ID: 33597508
PMC ID: PMC7890067
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.