Night shift work, melatonin, and circadian gene methylation in the development of breast cancer
Ritonja, Jennifer
Background: Night shift work is a prevalent work pattern in Canada. Epidemiologic studies suggest that long-term night shift work is associated with an increased risk of breast cancer, although methods and results widely vary among studies. In addition, the underlying molecular mechanisms linking night shift work and breast cancer are unclear. It is hypothesized that circadian disruption due to light at night exposure in night shift work can alter methylation in circadian genes, changing gene expression and increasing susceptibility to breast cancer. There is also evidence that melatonin can influence epigenetic mechanisms.
Objective: The overall aim of this thesis is to explore the role of night shift work, melatonin, and circadian gene methylation in the development of breast cancer.
Methods: A systematic review was conducted to assess the relationship between exposure to years of night shift work and risk of incident breast cancer. Incremental risk ratios for years of night shift work were calculated for each study, and combined in a dose-response meta-analysis. To examine the relationships between night shift work, melatonin and methylation of circadian genes, 74 female healthcare employees (n=38 day workers, n=36 night shift workers) who had urinary 6-sulfatoxymelatonin secretion data from a previous study were re-contacted. Newly collected blood samples were used to measure methylation at 1150 CpG loci across 22 circadian genes using the Illumina Infinium MethylationEPIC beadchip.
Results: For the meta-analysis, a non-linear dose-response relationship was found, where a 7% increase in breast cancer risk was seen after 20 years of exposure (95% CI: 1.01-1.15). In the cross-sectional study, findings suggest that night shift work is associated with differential methylation of the genes CSNK1E, NR1D1, and ARNTL. In the exploratory longitudinal study, findings suggest that melatonin is associated with changes in methylation of the genes MTNR1A, RORA, and PER3.
Conclusion: The meta-analysis findings suggest that increasing exposure to night shift work is associated with a higher risk of breast cancer, particularly after 20 years. In our studies, circadian misalignment, assessed by examining night shift work status and melatonin secretion patterns, is associated with differential methylation in circadian genes.
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