Abstract 4255: Imprintome-wide methylation alteration in human cancer: from occupation to clinic.
Authors: Jacobs Daniel I. , Hansen Johnni , Fu Alan , Stevens Richard G. , Tjonneland Anne , Vogel Ulla B. , Zheng Tongzhang , Mao Yingying , Kelly William K. , Zhu Yong 
Published: August 2014

Background: Exposure to light at night through shiftwork is a widespread occupational exposure which has been associated with cancer risk. In this study, we sought to investigate whether this association may be mediated in part by disruption of genomic imprinting patterns.

Methods: Using an Illumina Infinium Methylation Assay, we measured methylation differences at 397 CpG sites in the promoter regions of 56 imprinted genes in DNA isolated from 10 long-term shiftworkers as compared to 10 age- and folate intake-matched day workers. We subsequently measured methylation differences at these same CpG sites in a pooled sample of 12 pairs of prostate tumor as compared to adjacent normal tissue. Top differentially methylated loci were validated using the Sequenom EpiTYPER methylation assay.

Results: Among long-term shiftworkers, statistically significant hypermethylation was observed at 20 CpG sites and statistically significant hypomethylation was observed at 30 CpG sites relative to matched day workers (P &lt; 0.05). This differential methylation was observed across 26 unique genes, 15 of which contained CpG sites also statistically significantly differentially methylated between prostate tumor and adjacent normal tissue (P &lt; 0.05). In total, statistically significant hypermethylation was observed at 52 CpG sites and hypomethylation was observed at 17 CpG sites in prostate tumor relative to adjacent normal tissue. Of particular interest was the disruption of methylation patterns at TP73, an important component of the cellular apoptotic response, among both shiftworkers and in prostate tumor tissue. Tumor suppressor genes SLC22A18 and WT1 also demonstrated altered methylation patterns in both comparison groups. A query of publicly available expression array data returned several studies demonstrating statistically significant differential expression levels of these three genes in prostate cancer tissue relative to tissue from healthy controls.

Conclusion: In exploring the methylation patterns at normally imprinted genes among a set of shiftworkers and a sample of prostate tumor tissue, we have identified a set of 15 genes within which differential methylation is observed in comparison to day workers and adjacent normal prostate tissue, respectively. This altered methylation was observed at several important tumor suppressor genes, against a background of widespread changes in methylation at imprinted genes in both comparison groups. Taken together, these data suggest that loss of normal patterns of methylation at imprinted genes may be an important mechanism by which occupational exposure to light at night drives the increased risk of cancer development, and warrants further exploration.

Citation Format: Daniel I. Jacobs, Johnni Hansen, Alan Fu, Richard G. Stevens, Anne Tjonneland, Ulla B. Vogel, Tongzhang Zheng, Yingying Mao, William K. Kelly, Yong Zhu. Imprintome-wide methylation alteration in human cancer: from occupation to clinic. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4255. doi:10.1158/1538-7445.AM2013-4255