Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium.
There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3' of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (P(trend) = 1.5 × 10(-4)). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.
Canzian
Federico
F
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Cox
David G
DG
Setiawan
V Wendy
VW
Stram
Daniel O
DO
Ziegler
Regina G
RG
Dossus
Laure
L
Beckmann
Lars
L
Blanché
Hélène
H
Barricarte
Aurelio
A
Berg
Christine D
CD
Bingham
Sheila
S
Buring
Julie
J
Buys
Saundra S
SS
Calle
Eugenia E
EE
Chanock
Stephen J
SJ
Clavel-Chapelon
Françoise
F
DeLancey
John Oliver L
JO
Diver
W Ryan
WR
Dorronsoro
Miren
M
Haiman
Christopher A
CA
Hallmans
Göran
G
Hankinson
Susan E
SE
Hunter
David J
DJ
Hüsing
Anika
A
Isaacs
Claudine
C
Khaw
Kay-Tee
KT
Kolonel
Laurence N
LN
Kraft
Peter
P
Le Marchand
Loïc
L
Lund
Eiliv
E
Overvad
Kim
K
Panico
Salvatore
S
Peeters
Petra H M
PH
Pollak
Michael
M
Thun
Michael J
MJ
Tjønneland
Anne
A
Trichopoulos
Dimitrios
D
Tumino
Rosario
R
Yeager
Meredith
M
Hoover
Robert N
RN
Riboli
Elio
E
Thomas
Gilles
G
Henderson
Brian E
BE
Kaaks
Rudolf
R
Feigelson
Heather Spencer
HS
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D012739:Gonadal Steroid Hormones / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011786:Quality Control; D012307:Risk Factors; D014481:United States
D012739:Gonadal Steroid Hormones; D007334:Insulin-Like Growth Factor I