Abstract 4653: Can shift-work shift epigenetic patterns? – Genome-wide methylation profiling and cancer pathway analysis

Abstract

Abstract A substantial body of literature has recently linked circadian disruption to breast cancer risk, leading the International Agency for Research on Cancer (IARC) to conclude that “shift work involving circadian disruption is probably carcinogenic to humans”. Our previous epigenetic association analyses have also demonstrated differential promoter methylation in the core circadian genes in breast cancer cases relative to controls. However, the mechanistic connection between epigenetic changes associated with increased breast cancer and circadian disruption through exposure to ill-timed light has yet to be elucidated. In the current study, we investigated whether long term night shift work has significant effects on methylation patterns and whether genes exhibiting altered methylation states can affect cancer related pathways. Archived blood DNA samples of 117 female subjects from a prospective cohort conducted in Denmark were used for the analysis. Methylation of Alu repetitive elements, a proxy for global methylation, was measured using a PCR-based method. Genome-wide methylation analysis of 27,578 CpG sites, spanning 14,495 genes, was performed on the Illumina Infinium Methylation Chip. We first detected that methylation of Alu repetitive elements is significantly associated with exposure to long term (≥10 years) shift work (P=0.0353), indicating a global epigenetic impact of shift work. Genome-wide methylation analysis further discovered widespread methylation alterations (P<0.05 after adjustment for false discovery rate) in long term shift workers, including changes of many cancer-relevant transcripts. Finally, pathway analysis found that genes with altered methylation patterns form several cancer-related networks (P<0.005), including pathways relevant to “p53 signaling” and “Telomeres, telomerase, cellular aging and immortality”. These results demonstrate for the first time the existence of genome-wide epigenetic consequences of shift work and their cancer relevance, which may break new ground in understanding the clock-cancer connection by elucidating a novel mechanism by which exposure to occupations involving shift work may influence epigenetic phenotypes. These findings may also advance our understanding of the role of ill-timed light in carcinogenesis and could have widespread implications in the areas of environmental oncology, cancer epigenetics, and occupational health. Considering that millions of women worldwide are being exposed to ill-timed light through exposure to shift work, greater understanding of the effects of this exposure is urgently required, which may lead to new policies for shift workers and novel strategies for cancer prevention. This work was supported by NIEHS grant ES018915 and funds from the Danish Cancer Society. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2011-4653