Abstract
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
Highlights
Both genetic and non-genetic factors are involved in the etiology of breast cancer
We used pooled data from 24 studies participating in the Breast Cancer Association Consortium (BCAC) to evaluate whether the relative risks of single nucleotide polymorphisms (SNPs) at 23 published loci vary according to levels of 10 established environmental risk factors [8]
Based on 18,532 cases and 25,341 controls from 16 populationbased studies, we found the expected associations between the environmental risk factors and breast cancer risk (Table 2)
Summary
Both genetic and non-genetic factors are involved in the etiology of breast cancer. Known susceptibility variants include rare highrisk mutations, principally in BRCA1 and BRCA2, more moderate susceptibility variants in genes such as PALB2, CHEK2 and ATM, and more than 20 common genetic susceptibility variants conferring modest increased risks, principally identified through genome-wide association studies. There is still limited knowledge about how the relative risks of common susceptibility loci might be modified by the established reproductive and lifestyle risk factors (referred to as environmental risk factors) for breast cancer. The strongest previously reported findings were for an interaction between LSP1rs3817198 and number of births (P-value = 0.002), between CASP8rs104585 and alcohol consumption (P-value = 0.003), and between 5p12-rs10941679 and use of estrogen-only MHT (P-value = 0.007) [2,6,7] This lack of statistical evidence of interaction beyond that expected by chance may be partly due to limited power to detect weak gene-environment interactions and not having considered specific subtypes of breast cancer. Since there is etiologic heterogeneity by subtypes of breast cancer, we carried out these assessments for breast cancer with positive and negative estrogen receptor (ER) status [9]
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