Global DNA methylation of WTC prostate cancer tissues show signature differences compared to non-exposed cases

Abstract

There is increased incidence of prostate cancer (PC) among World Trade Center (WTC)-exposed responders and community members, with preliminary evidence suggestive of more aggressive disease. While previous research is supportive of differences in DNA methylation and gene expression as a consequence of WTC exposure, as measured in blood of healthy individuals, the epigenetics of WTC PC tissues has yet to be explored. Patients were recruited from the World Trade Center Health Program. Non-WTC PC samples were frequency matched on age, race/ethnicity and Gleason score. Bisulfite-treated DNA was extracted from tumor tissue blocks and used to assess global DNA methylation with the MethylationEPIC BeadChip. Differential and pathway enrichment analysis were conducted. RNA from the same tumor blocks was used for gene expression analysis to further support DNA methylation findings. Methylation data were generated for 28 samples (13 WTC and 15 non-WTC). Statistically significant differences in methylation were observed for 3,586 genes; on average WTC samples were statistically significantly more hypermethylated (p=0.04131). Pathway enrichment analysis revealed hypermethylation in epithelial mesenchymal transition (EMT), hypoxia, mitotic spindle, TNFA signaling via NFKB, WNT signaling, and TGF beta signaling pathways in WTC compared to non-WTC samples. The androgen response, G2M and MYC target pathways were hypomethylated. These results correlated well with RNA gene expression. In conclusion, long-term epigenic changes associated with WTC dust exposure were observed in PC tissues. These occurred in genes of critical pathways, likely increasing prostate tumorigenesis potential. This warrants analysis of larger WTC groups and other cancer types.

Genome-wide DNA methylation profiles and breast cancer among World Trade Center survivors

“… 61 It is worth noting, however, that several classes of gene pathways reported as overrepresented among WTC-exposed breast cancer cases have been consistently observed, both in our previous pilot studies of WTC exposure among cancer-free women 27 and breast cancer cases, 28 but also in an analysis of the DNA methylation profiles of WTC-exposed versus unexposed prostate cancer cases. 62 These included immune system-related gene pathways, as well as those related to cancer and cell mobility alterations. 63 Interestingly, the endocytosis pathways were consistently observed to be dysregulated among WTC-exposed individuals.…”

World Trade Center Exposure, DNA Methylation Changes, and Cancer: A Review of Current Evidence

“…We previously described epigenetic profiles from the blood of cancer-free WTC Survivors [35] as well as Survivors with breast cancer [36] and prostate tumor tissue of Responders [37]. In each of these epigenome-wide association studies (EWAS), we found evidence of global and site-specific WTC-associated DNA methylation changes.…”

“…Pathologist review and microdissection were performed to ensure that tumor cells comprised more than 80% of formalinfixed paraffin-embedded (FFPE) tumor tissue samples. DNA was extracted, restored, and bisulfite-treated before being hybridized to the MethylationEPIC array BeadChip (Illumina Inc., San Diego, CA, USA) [37].…”

“…Three out of four studies [35][36][37] used the same Infinium Methylation EPIC array (Illumina ® ) BeadChip to determine the DNA methylation status of 866,562 CpG sites [46]. Probes were quantile-normalized, background-adjusted, and adjusted for multiple testing.…”

“…Ultimately, cancers can result from a joint accumulation of epigenetic alterations and genetic mutations [34]. Given the chemical makeup of the WTC dust, we [35][36][37] and others [38] have hypothesized that WTC dust exposure results in global, long-term epigenetic alterations capable of promoting tumorigenesis.…”