Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

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.

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes

“…28 Consortium-based analyses may be particularly useful for detecting variants modified by weak-tomoderate gene-environment interactions. 29 Meta-analysis has also become increasingly popular in GWAS, 30 where it can aid in exploring the heterogeneity across data sets and identifying more disease-related genes. 31 In 2011, there were 173 publications on metaanalyses and pooled analyses of candidate genes in cancer, and 39 GWAS, of which 6 included a meta-analysis.…”

Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers

“…The general approach to work around this problem has been to assume that these factors act independently in modifying risk, unless evidence to the contrary is observed. Although statistical power to detect deviations from log-additive combined effects is limited, studies in the general population have consistently found very little evidence of these (Milne et al 2010a,b, Travis et al 2010, Campa et al 2011, Nickels et al 2013, Rudolph et al 2015. Prospective studies will be essential to assess the validity of this assumption and of the risk prediction models more generally.…”

Two nonsynonymous polymorphisms (F31I and V57I) of theSTK15gene and breast cancer risk: A meta-analysis based on 5966 cases and 7609 controls

“…1 The mechanism of breast carcinogenesis is still not fully understood, but breast cancers are generally considered to result from interactions between multiple environmental, dietary, hereditary, racial and socioeconomic risk factors. 2 Aurora kinase A, which is encoded by the STK15 gene (also known as BTAK), is involved in cell-cycle regulation, in particular the passage from G 2 to M, through the formation of mitotic spindles. 3 Due to this regulatory function, the STK15 gene has been hypothesized to be a potential cancer susceptibility gene.…”