Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
BACKGROUND
Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.


METHODS
We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.


RESULTS
SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018).


CONCLUSIONS
This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia. logan.walker@qimr.edu.au
Logan C
LC
Walker
Zachary S
ZS
Fredericksen
Xianshu
X
Wang
Robert
R
Tarrell
Vernon S
VS
Pankratz
Noralane M
NM
Lindor
Jonathan
J
Beesley
Sue
S
Healey
Xiaoqing
X
Chen
Dominique
D
Stoppa-Lyonnet
Carole
C
Tirapo
Sophie
S
Giraud
Sylvie
S
Mazoyer
Danièle
D
Muller
Jean-Pierre
JP
Fricker
Capucine
C
Delnatte
Rita K
RK
Schmutzler
Barbara
B
Wappenschmidt
Christoph
C
Engel
Ines
I
Schönbuchner
Helmut
H
Deissler
Alfons
A
Meindl
Frans B
FB
Hogervorst
Martijn
M
Verheus
Maartje J
MJ
Hooning
Ans Mw
AM
van den Ouweland
Marcel R
MR
Nelen
Margreet Gem
MG
Ausems
Cora M
CM
Aalfs
Christi J
CJ
van Asperen
Peter
P
Devilee
Monique M
MM
Gerrits
Quinten
Q
Waisfisz
Csilla I
CI
Szabo
Douglas F
DF
Easton
Susan
S
Peock
Margaret
M
Cook
Clare T
CT
Oliver
Debra
D
Frost
Patricia
P
Harrington
D Gareth
DG
Evans
Fiona
F
Lalloo
Ros
R
Eeles
Louise
L
Izatt
Carol
C
Chu
Rosemarie
R
Davidson
Diana
D
Eccles
Kai-Ren
KR
Ong
Jackie
J
Cook
Tim
T
Rebbeck
Katherine L
KL
Nathanson
Susan M
SM
Domchek
Christian F
CF
Singer
Daphne
D
Gschwantler-Kaulich
Anne-Catharina
AC
Dressler
Georg
G
Pfeiler
Andrew K
AK
Godwin
Tuomas
T
Heikkinen
Heli
H
Nevanlinna
Bjarni A
BA
Agnarsson
Maria Adelaide
MA
Caligo
Håkan
H
Olsson
Ulf
U
Kristoffersson
Annelie
A
Liljegren
Brita
B
Arver
Per
P
Karlsson
Beatrice
B
Melin
Olga M
OM
Sinilnikova
Lesley
L
McGuffog
Antonis C
AC
Antoniou
Georgia
G
Chenevix-Trench
Amanda B
AB
Spurdle
Fergus J
FJ
Couch
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics
D051900:Smad3 Protein; D016212:Transforming Growth Factor beta