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.

Author(s): Canzian F,  Cox DG,  Setiawan VW,  Stram DO,  Ziegler RG,  Dossus L,  Beckmann L,  Blanché H,  Barricarte A,  Berg CD,  Bingham S,  Buring J,  Buys SS,  Calle EE,  Chanock SJ,  Clavel-Chapelon F,  DeLancey JO,  Diver WR,  Dorronsoro M,  Haiman CA,  Hallmans G,  Hankinson SE,  Hunter DJ,  Hüsing A,  Isaacs C,  Khaw KT,  Kolonel LN,  Kraft P,  Le Marchand L,  Lund E,  Overvad K,  Panico S,  Peeters PH,  Pollak M,  Thun MJ,  Tjønneland A,  Trichopoulos D,  Tumino R,  Yeager M,  Hoover RN,  Riboli E,  Thomas G,  Henderson BE,  Kaaks R,  Feigelson HS

Journal: Hum Mol Genet

Date: 2010 Oct 1

Major Program(s) or Research Group(s): EDRG, PLCO

PubMed ID: 20634197

PMC ID: PMC2935856

Abstract: 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.