Global DNA Methylation Profiles in Peripheral Blood of WTC-Exposed Community Members with Breast Cancer

Abstract

Breast cancer represents the most common cancer diagnosis among World Trade Center (WTC)-exposed community members, residents, and cleanup workers enrolled in the WTC Environmental Health Center (WTC EHC). The primary aims of this study were (1) to compare blood DNA methylation profiles of WTC-exposed community members with breast cancer and WTC-unexposed pre-diagnostic breast cancer blood samples, and (2) to compare the DNA methylation differences among the WTC EHC breast cancer cases and WTC-exposed cancer-free controls. Gene pathway enrichment analyses were further conducted. There were significant differences in DNA methylation between WTC-exposed breast cancer cases and unexposed prediagnostic breast cancer cases. The top differentially methylated genes were Intraflagellar Transport 74 (IFT74), WD repeat-containing protein 90 (WDR90), and Oncomodulin (OCM), which are commonly upregulated in tumors. Probes associated with established tumor suppressor genes (ATM, BRCA1, PALB2, and TP53) were hypermethylated among WTC-exposed breast cancer cases compared to the unexposed group. When comparing WTC EHC breast cancer cases vs. cancer-free controls, there appeared to be global hypomethylation among WTC-exposed breast cancer cases compared to exposed controls. Functional pathway analysis revealed enrichment of several gene pathways in WTC-exposed breast cancer cases including endocytosis, proteoglycans in cancer, regulation of actin cytoskeleton, axon guidance, focal adhesion, calcium signaling, cGMP-PKG signaling, mTOR, Hippo, and oxytocin signaling. The results suggest potential epigenetic links between WTC exposure and breast cancer in local community members enrolled in the WTC EHC program.

Keywords: 9/11; World Trade Center; breast cancer; environmental exposure; epigenome-wide association study; exposure assessment; methylation; pathway analysis.

Figure 1

Functional genomic pathways enriched in the WTC-exposed (WTC EHC) breast cancer cases vs. unexposed (NYUWHS) breast cancer cases. Legend: Summary of pathway network analysis highlights the relationship between probe sets enriched in the WTC-exposed women compared to unexposed women. Y-axis shows the probe sets with significant overlap with the reference probe sets/genes from the KEGG database. X-axis shows the ratio of the number of differentially expressed probe sets/genes to the total number of genes included in the particular pathway gene set from the reference KEGG pathway database. The dot sizes are proportional to the number of overlapping probe sets/genes. The dot colors show the p-value adjusted for false discovery rate.

Figure 2

Functional genomic pathways enriched in the WTC-exposed (WTC EHC) breast cancer cases vs. WTC-exposed cancer-free women. Legend: Summary of pathway network analysis highlights the relationship between probe sets enriched in the WTC-exposed women compared to unexposed women. Y-axis shows the probe sets with significant overlap with the reference probe sets/genes from the KEGG database. X-axis shows the ratio of the number of differentially expressed probe sets/genes to the total number of genes included in the particular pathway gene set from the reference KEGG pathway database. The dot sizes are proportional to the number of overlapping probe sets/genes. The dot colors show the p-value adjusted for false discovery rate.