Gene-Environment Interactions in 7610 Women With Breast Cancer: Prospective Evidence From the Million Women Study

Abstract

Both genetic and environmental factors contribute to the risk of breast cancer but it is unclear whether specific gene-environment interactions increase risk. Genome-wide association studies identified a number of breast cancer low-penetrance genetic susceptibility polymorphisms. There are scant data on the combined effects of these polymorphisms and environmental factors on the incidence of breast cancer. Some studies suggested possible interactions between some genetic susceptibility polymorphisms and use of hormone replacement therapy (HRT) or breast cancer, but the data were inconsistent. The aim of this prospective cohort study was to determine whether environmental risk factors modified the relative risks of breast cancer associated with several single nucleotide polymorphisms (SNPs) previously associated with the disease. Routine screening for breast cancer was performed at 66 screening centers in the United Kingdom during 1996-2001 in 1.3 million women (mean age, 56 years). The study participants were 7610 women who developed breast cancer and 10,196 randomly selected women without breast cancer. The investigators tested the association between 10 established environmental risk factors for breast cancer (age at menarche, parity, age at first birth, breast-feeding, menopausal status, age at menopause, use of HRT, body-mass index, height, and alcohol consumption) and 12 SNPs (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs 13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8- rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB 1- rs 1982073, and ATM-rs 1800054). Logistic regression models were used to determine the main effect of each of the 12 SNPs on the relative risk for breast cancer by calculating the per-allele age-adjusted relative risks for the high-risk versus the low-risk allele. The data showed that none of 120 possible gene-environment interactions in 7610 women with breast cancer remained significant after allowance for the multiple tests. There was little evidence for interactions between genotype, use of HRT, and estrogen-receptor-positive breast cancer. After adjustment for multiple testing, no significant associations were found between 11 of the 12 polymorphisms and the 10 environmental risk factors. A significant association was found for only 1 of the 12 polymorphisms: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than noncarriers; the mean heights of carriers versus noncarriers were 162 ± 4 cm (95% confidence interval: 162.1-162.7) and 163 ± 1 cm (162.9-163.2), respectively, after adjustment for multiple testing (P = 0.01). These findings show no significant increased risk of breast cancer associated with low-penetrance susceptibility polymorphisms for 10 established environmental risk factors.