Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study

• Authors: Tengteng Wang, University of North Carolina; Lauren McCullough, Emory University; Alexandra J. White, NIEHS; Patrick T. Bradshaw, University of California Berkeley; Xinran Xu, Roche Product Development in Asia-Pacific; Yoon Hee Cho, University of Montana; Mary Beth Terry, Columbia University; Susan L. Teitelbaum, Icahn School of Medicine at Mount Sinai; Alfred I. Neugut, Columbia University; Regina M. Santella, Columbia University; Jia Chen, Icahn School of Medicine at Mount Sinai; Marilie D. Gammon, University of North Carolina
• Journal Title: Cancer
• Volume: Volume 125, Number 21
• Publisher: Wiley | 2019-08-12, Pages 3836-3844
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/cncr.32364
• Subjects: Health Sciences, Oncology; Biology, Genetics; Health Sciences, Epidemiology; Engineering, Biomedical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; aspirin; breast cancer; DNA methylation; epigenetic; mortality; Nonsteroidal anti-inflammatory agents; Promoter hypermethylation; COX-2 Expression; Poor prognosis; Association; Hypomethylation; Survival; Receptor; Women

Abstract

BACKGROUND: We hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. Ours is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS: Pre-diagnosis aspirin use was assessed through in-person interviews within the population-based cohort of 1,508 women diagnosed with first primary breast cancer in 1996-1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of thirteen breast cancer-related genes was measured in tumor by methylation-specific PCR and Methyl Light. Vital status was determined by the National Death Index through December 31, 2014 (N=237/597 breast cancer-specific/all-cause deaths identified). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs), and the likelihood ratio test to evaluate multiplicative interaction. RESULTS: All-cause mortality was elevated among aspirin users with methylated promotor of BRCA1 (HR=1.67; 95%CI=1.26–2.22), but not among those with unmethylated BRCA1 (HR=0.99; 95%CI=0.67–1.45) (pinteraction≤0.05). Decreased breast cancer-specific mortality was found among aspirin users with unmethylated promotor of BRCA1 and PR, and LINE-1 global hypermethylation (HR=0.60, 0.78, and 0.63, respectively; pinteraction≤0.05), although the 95%CIs included the null. CONCLUSIONS: Our current study suggests that the LINE-1 global methylation, and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality following breast cancer.