Polycyclic aromatic hydrocarbon (PAH)–DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study

Purpose: Polycyclic aromatic hydrocarbon (PAH)–DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH–DNA adducts, methylation, and breast cancer are unknown. The objectives of this study were to (1) assess associations between PAH–DNA adducts, and breast cancer, stratified by DNA methylation markers and (2) examine interactions between adducts and DNA methylation in association with breast cancer and tumor subtype. Methods: In a population-based case–control study, promoter methylation of 13 breast cancer-related genes was measured in tumor tissue (n = 765–851 cases). Blood DNA from breast cancer cases (n = 873) and controls (n = 941) was used to assess PAH–DNA adducts and global methylation. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95 % confidence intervals (CI); and the ratio of the OR (ROR) was used to assess heterogeneity. Results: Women with detectable PAH–DNA adducts and methylated RARβ (ROR 2.69, 95 % CI 1.02–7.12; p for interaction = 0.03) or APC (ROR 1.76, 95 % CI 0.87–3.58; p for interaction = 0.09) genes were more likely to have hormone receptor-positive tumors than other subtypes. Interactions with other methylation markers were not apparent (p ≥ 0.10). The association between adducts and breast cancer did not vary by methylation status of the tumor nor did adducts associate with global methylation in the controls. Conclusions: Gene-specific methylation of RARβ, and perhaps APC, may interact with PAH–DNA adducts to increase risk of hormone receptor-positive breast cancer. There was little evidence that adducts were associated with or interacted with other methylation markers of interest.