Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
Department of Epidemiology and Population Health and Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, New York, New York, United States of America.
Mia M
MM
Gaudet
Tomas
T
Kirchhoff
Todd
T
Green
Joseph
J
Vijai
Joshua M
JM
Korn
Candace
C
Guiducci
Ayellet V
AV
Segrè
Kate
K
McGee
Lesley
L
McGuffog
Christiana
C
Kartsonaki
Jonathan
J
Morrison
Sue
S
Healey
Olga M
OM
Sinilnikova
Dominique
D
Stoppa-Lyonnet
Sylvie
S
Mazoyer
Marion
M
Gauthier-Villars
Hagay
H
Sobol
Michel
M
Longy
Marc
M
Frenay
GEMO Study Collaborators
Frans B L
FB
Hogervorst
Matti A
MA
Rookus
J Margriet
JM
Collée
Nicoline
N
Hoogerbrugge
Kees E P
KE
van Roozendaal
Marion
M
Piedmonte
Wendy
W
Rubinstein
Stacy
S
Nerenstone
Linda
L
Van Le
Stephanie V
SV
Blank
Trinidad
T
Caldés
Miguel
M
de la Hoya
Heli
H
Nevanlinna
Kristiina
K
Aittomäki
Conxi
C
Lazaro
Ignacio
I
Blanco
Adalgeir
A
Arason
Oskar T
OT
Johannsson
Rosa B
RB
Barkardottir
Peter
P
Devilee
Olofunmilayo I
OI
Olopade
Susan L
SL
Neuhausen
Xianshu
X
Wang
Zachary S
ZS
Fredericksen
Paolo
P
Peterlongo
Siranoush
S
Manoukian
Monica
M
Barile
Alessandra
A
Viel
Paolo
P
Radice
Catherine M
CM
Phelan
Steven
S
Narod
Gad
G
Rennert
Flavio
F
Lejbkowicz
Anath
A
Flugelman
Irene L
IL
Andrulis
Gord
G
Glendon
Hilmi
H
Ozcelik
Amanda E
AE
Toland
Marco
M
Montagna
Emma
E
D'Andrea
Eitan
E
Friedman
Yael
Y
Laitman
Ake
A
Borg
Mary
M
Beattie
Susan J
SJ
Ramus
Susan M
SM
Domchek
Katherine L
KL
Nathanson
Tim
T
Rebbeck
Amanda B
AB
Spurdle
Xiaoqing
X
Chen
Helene
H
Holland
Esther M
EM
John
John L
JL
Hopper
Saundra S
SS
Buys
Mary B
MB
Daly
Melissa C
MC
Southey
Mary Beth
MB
Terry
Nadine
N
Tung
Thomas V
TV
Overeem Hansen
Finn C
FC
Nielsen
Mark H
MH
Greene
Mark I
MI
Greene
Phuong L
PL
Mai
Ana
A
Osorio
Mercedes
M
Durán
Raquel
R
Andres
Javier
J
Benítez
Jeffrey N
JN
Weitzel
Judy
J
Garber
Ute
U
Hamann
Susan
S
Peock
Margaret
M
Cook
Clare
C
Oliver
Debra
D
Frost
Radka
R
Platte
D Gareth
DG
Evans
Fiona
F
Lalloo
Ros
R
Eeles
Louise
L
Izatt
Lisa
L
Walker
Jacqueline
J
Eason
Julian
J
Barwell
Andrew K
AK
Godwin
Rita K
RK
Schmutzler
Barbara
B
Wappenschmidt
Stefanie
S
Engert
Norbert
N
Arnold
Dorothea
D
Gadzicki
Michael
M
Dean
Bert
B
Gold
Robert J
RJ
Klein
Fergus J
FJ
Couch
Georgia
G
Chenevix-Trench
Douglas F
DF
Easton
Mark J
MJ
Daly
Antonis C
AC
Antoniou
David M
DM
Altshuler
Kenneth
K
Offit
D000328:Adult; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10; D002890:Chromosomes, Human, Pair 20; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C475725:ZNF365 protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2