Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.
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.
Antoniou
Antonis C
AC
Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK. antonis@srl.cam.ac.uk
Spurdle
Amanda B
AB
Sinilnikova
Olga M
OM
Healey
Sue
S
Pooley
Karen A
KA
Schmutzler
Rita K
RK
Versmold
Beatrix
B
Engel
Christoph
C
Meindl
Alfons
A
Arnold
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N
Hofmann
Wera
W
Sutter
Christian
C
Niederacher
Dieter
D
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Helmut
H
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Trinidad
T
Kämpjärvi
Kati
K
Nevanlinna
Heli
H
Simard
Jacques
J
Beesley
Jonathan
J
Chen
Xiaoqing
X
Neuhausen
Susan L
SL
Rebbeck
Timothy R
TR
Wagner
Theresa
T
Lynch
Henry T
HT
Isaacs
Claudine
C
Weitzel
Jeffrey
J
Ganz
Patricia A
PA
Daly
Mary B
MB
Tomlinson
Gail
G
Olopade
Olufunmilayo I
OI
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Joanne L
JL
Couch
Fergus J
FJ
Peterlongo
Paolo
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Manoukian
Siranoush
S
Barile
Monica
M
Radice
Paolo
P
Szabo
Csilla I
CI
Pereira
Lutecia H Mateus
LH
Greene
Mark H
MH
Rennert
Gad
G
Lejbkowicz
Flavio
F
Barnett-Griness
Ofra
O
Andrulis
Irene L
IL
Ozcelik
Hilmi
H
Gerdes
Anne-Marie
AM
Caligo
Maria A
MA
Laitman
Yael
Y
Kaufman
Bella
B
Milgrom
Roni
R
Friedman
Eitan
E
Domchek
Susan M
SM
Nathanson
Katherine L
KL
Osorio
Ana
A
Llort
Gemma
G
Milne
Roger L
RL
Benítez
Javier
J
Hamann
Ute
U
Hogervorst
Frans B L
FB
Manders
Peggy
P
Ligtenberg
Marjolijn J L
MJ
van den Ouweland
Ans M W
AM
Peock
Susan
S
Cook
Margaret
M
Platte
Radka
R
Evans
D Gareth
DG
Eeles
Rosalind
R
Pichert
Gabriella
G
Chu
Carol
C
Eccles
Diana
D
Davidson
Rosemarie
R
Douglas
Fiona
F
Godwin
Andrew K
AK
Barjhoux
Laure
L
Mazoyer
Sylvie
S
Sobol
Hagay
H
Bourdon
Violaine
V
Eisinger
François
F
Chompret
Agnès
A
Capoulade
Corinne
C
Bressac-de Paillerets
Brigitte
B
Lenoir
Gilbert M
GM
Gauthier-Villars
Marion
M
Houdayer
Claude
C
Stoppa-Lyonnet
Dominique
D
Chenevix-Trench
Georgia
G
Easton
Douglas F
DF
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
C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human