Abstract 160: Identifying differential methylation patterns of benign and tumor prostate tissue in African American and European American prostate cancer patients
Authors: Chernoff Meytal B. , Demanelis Kathryn , Gillard Marc , Delgado Dayana , Griend Donald J. Vander , Pierce Brandon L. 
Published: September 2020

This study aims to identify biological features and processes underlying disparities in prostate cancer (PCa) between African American (AA) and European American (EA) men using DNA methylation (DNAm). Changes in genome-wide DNAm accompany tumor development and progression. Differences in genome-wide DNAm across ancestry groups may be an important mechanism to understand the higher incidence and poorer prognosis among AA men. We collected paired tumor and histologically benign tissue from formalin fixed and paraffin embedded (FFPE) blocks from 150 prostate cancer patients (75 AA, 75 EA) at the University of Chicago. DNA was extracted and genome-wide DNAm was measured at ~850,000 CpG sites in benign and tumor tissue using the Illumina Infinium MethylationEpic BeadChip. After CpG and sample-level QC and normalization, we conducted differential methylation analyses, comparing tumor and benign tissue within each ancestry group, adjusting for batch, age, and tissue pair. We then used Gene Set Enrichment Analysis (GSEA) to examine enrichment of GO and Hallmark terms. 682,694 CpGs passed QC filtering. For AA and EA, CpGs hyper-methylated in cancer tissue were enriched in CpG islands while hypo-methylated CpGs were enriched in open seas. We identified 39,768 and 25,405 tumor-associated CpGs in AA and EA respectively (p&lt;5 × 10-8 and absolute change in methylation 0.25). Of these, 23,068 CpGs were common to both sets. In AA, a higher proportion of tumor-associated CpGs were hypo-methylated compared to EA (40.5% vs 18.6%, p&lt;2 × 10-16). A larger proportion tumor-associated CpGs annotated to non-CpG islands in AA compared to EA (67.7% vs 62%) (p=2 × 10-16). We also observed an increased proportion of differentially methylated CpGs in promoter regions in EA compared with AA. Consistent with prior studies, among the common, tumor-associated CpGs, we observed differential methylation of GSTP1 and APC, both involved in PCa development. We observed enrichment in 6 genesets in both AA and EA, including the epithelial mesenchymal transition and estrogen response. In AA we observed additional enrichment in 2 genesets including hedgehog signaling (FDR&lt;0.05). Comparing the ancestry groups, adjusting for age and batch, we found 219 differentially methylated CpGs between AA and EA in tumor and 151 in benign tissue. Overall, we identified higher frequencies of differential methylation and more differentially methylated genes in AA compared with EA; despite slightly more favorable clinical features in the AA in our sample. We also found differential methylation by ancestry within each tissue type. These results suggest the existence of epigenetic alterations unique to AA and EA that may contribute to the biological basis of PCa disparities. Moving forward we will refine our analyses, adjusting for cell type proportion and further examining the differentially methylated pathways.

Citation Format: Meytal B. Chernoff, Kathryn Demanelis, Marc Gillard, Dayana Delgado, Donald J. Vander Griend, Brandon L. Pierce. Identifying differential methylation patterns of benign and tumor prostate tissue in African American and European American prostate cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 160.