title: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.
abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.
authors: Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK. antonis@srl.cam.ac.uk
authors: Antonis C
authors: AC
authors: Antoniou
authors: Amanda B
authors: AB
authors: Spurdle
authors: Olga M
authors: OM
authors: Sinilnikova
authors: Sue
authors: S
authors: Healey
authors: Karen A
authors: KA
authors: Pooley
authors: Rita K
authors: RK
authors: Schmutzler
authors: Beatrix
authors: B
authors: Versmold
authors: Christoph
authors: C
authors: Engel
authors: Alfons
authors: A
authors: Meindl
authors: Norbert
authors: N
authors: Arnold
authors: Wera
authors: W
authors: Hofmann
authors: Christian
authors: C
authors: Sutter
authors: Dieter
authors: D
authors: Niederacher
authors: Helmut
authors: H
authors: Deissler
authors: Trinidad
authors: T
authors: Caldes
authors: Kati
authors: K
authors: Kämpjärvi
authors: Heli
authors: H
authors: Nevanlinna
authors: Jacques
authors: J
authors: Simard
authors: Jonathan
authors: J
authors: Beesley
authors: Xiaoqing
authors: X
authors: Chen
authors: Susan L
authors: SL
authors: Neuhausen
authors: Timothy R
authors: TR
authors: Rebbeck
authors: Theresa
authors: T
authors: Wagner
authors: Henry T
authors: HT
authors: Lynch
authors: Claudine
authors: C
authors: Isaacs
authors: Jeffrey
authors: J
authors: Weitzel
authors: Patricia A
authors: PA
authors: Ganz
authors: Mary B
authors: MB
authors: Daly
authors: Gail
authors: G
authors: Tomlinson
authors: Olufunmilayo I
authors: OI
authors: Olopade
authors: Joanne L
authors: JL
authors: Blum
authors: Fergus J
authors: FJ
authors: Couch
authors: Paolo
authors: P
authors: Peterlongo
authors: Siranoush
authors: S
authors: Manoukian
authors: Monica
authors: M
authors: Barile
authors: Paolo
authors: P
authors: Radice
authors: Csilla I
authors: CI
authors: Szabo
authors: Lutecia H Mateus
authors: LH
authors: Pereira
authors: Mark H
authors: MH
authors: Greene
authors: Gad
authors: G
authors: Rennert
authors: Flavio
authors: F
authors: Lejbkowicz
authors: Ofra
authors: O
authors: Barnett-Griness
authors: Irene L
authors: IL
authors: Andrulis
authors: Hilmi
authors: H
authors: Ozcelik
authors: Anne-Marie
authors: AM
authors: Gerdes
authors: Maria A
authors: MA
authors: Caligo
authors: Yael
authors: Y
authors: Laitman
authors: Bella
authors: B
authors: Kaufman
authors: Roni
authors: R
authors: Milgrom
authors: Eitan
authors: E
authors: Friedman
authors: Susan M
authors: SM
authors: Domchek
authors: Katherine L
authors: KL
authors: Nathanson
authors: Ana
authors: A
authors: Osorio
authors: Gemma
authors: G
authors: Llort
authors: Roger L
authors: RL
authors: Milne
authors: Javier
authors: J
authors: Benítez
authors: Ute
authors: U
authors: Hamann
authors: Frans B L
authors: FB
authors: Hogervorst
authors: Peggy
authors: P
authors: Manders
authors: Marjolijn J L
authors: MJ
authors: Ligtenberg
authors: Ans M W
authors: AM
authors: van den Ouweland
authors: Susan
authors: S
authors: Peock
authors: Margaret
authors: M
authors: Cook
authors: Radka
authors: R
authors: Platte
authors: D Gareth
authors: DG
authors: Evans
authors: Rosalind
authors: R
authors: Eeles
authors: Gabriella
authors: G
authors: Pichert
authors: Carol
authors: C
authors: Chu
authors: Diana
authors: D
authors: Eccles
authors: Rosemarie
authors: R
authors: Davidson
authors: Fiona
authors: F
authors: Douglas
authors: Andrew K
authors: AK
authors: Godwin
authors: Laure
authors: L
authors: Barjhoux
authors: Sylvie
authors: S
authors: Mazoyer
authors: Hagay
authors: H
authors: Sobol
authors: Violaine
authors: V
authors: Bourdon
authors: François
authors: F
authors: Eisinger
authors: Agnès
authors: A
authors: Chompret
authors: Corinne
authors: C
authors: Capoulade
authors: Brigitte
authors: B
authors: Bressac-de Paillerets
authors: Gilbert M
authors: GM
authors: Lenoir
authors: Marion
authors: M
authors: Gauthier-Villars
authors: Claude
authors: C
authors: Houdayer
authors: Dominique
authors: D
authors: Stoppa-Lyonnet
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Douglas F
authors: DF
authors: Easton
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D012306:Risk
chemical_list: C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human