IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).
IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.
Patel
Alpa V
AV
Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia, United States of America. apatel@cancer.org
Cheng
Iona
I
Canzian
Federico
F
Le Marchand
Loïc
L
Thun
Michael J
MJ
Berg
Christine D
CD
Buring
Julie
J
Calle
Eugenia E
EE
Chanock
Stephen
S
Clavel-Chapelon
Francoise
F
Cox
David G
DG
Dorronsoro
Miren
M
Dossus
Laure
L
Haiman
Christopher A
CA
Hankinson
Susan E
SE
Henderson
Brian E
BE
Hoover
Robert
R
Hunter
David J
DJ
Kaaks
Rudolf
R
Kolonel
Laurence N
LN
Kraft
Peter
P
Linseisen
Jakob
J
Lund
Eiliv
E
Manjer
Jonas
J
McCarty
Catherine
C
Peeters
Petra H M
PH
Pike
Malcolm C
MC
Pollak
Michael
M
Riboli
Elio
E
Stram
Daniel O
DO
Tjonneland
Anne
A
Travis
Ruth C
RC
Trichopoulos
Dimitrios
D
Tumino
Rosario
R
Yeager
Meredith
M
Ziegler
Regina G
RG
Feigelson
Heather Spencer
HS
D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000235:genetics*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics; D012307:Risk Factors
D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I