Abstract 7004: DNA Methylation analysis of African American colorectal cancers reveal race-specific alterations

Abstract African Americans (AAs) have among the highest incidence and mortality rates of colorectal cancer (CRC) in the US. They present with more right-sided, microsatellite stable (MSS) tumors and are diagnosed at earlier ages than non-Hispanic Whites (NHW). While DNA methylation changes and their significance have been previously described in CRC, much less is known about the unique DNA methylation changes that occur in AA CRCs compared to NHW CRCs. In the current study, we analyzed DNA methylation changes in AA patients and compared those changes to data from NHWs. AA patients diagnosed with a MSS colorectal tumor at the Yale New Health System were included in the study. A pathologist reviewed archival slides, and selected areas from CRCs (n=160) and adjacent normal tissue (n=42) were cored (median age=59; 82 females, 78 males). DNA was bisulfite converted and analysis performed using EPIC arrays. The 450K methylation array from NHW CRCs was also analyzed for 217 CRCs and 20 normal tissues obtained from TCGA (median age=68; 103 females, 114 males). Differentially methylated regions (DMRs) with |Δβ|>0.1, FDR corrected p-value <0.05 between tumor and normal tissue were identified using SeSAMe. We identified 4881 DMRs (57% hyper- and 44% hypomethylated) between AA CRC and normal tissue. Of these, 46% were in CpG Islands, 15% in CpG Shores, 4% in CpG shelves, and 36% in open sea. Most DMRs (71%) were in promoter regions, with 18% in gene bodies, 5% in enhancer regions, and 6% in intergenic regions. Next, we performed additional DMR analysis using overlapping probes from both arrays to compare NHW with AA data. We identified 2239 DMRs between AA CRC and normal tissue compared to 4138 in NHW. Of the 2239 AA DMRs, 1419 (66%) were common with NHW DMRs, 790 (34%) were unique to AAs. There were many overlapping pathways and genes; however, the DMRs impacting these pathways differed between AA and NHW CRCs. Hypermethylation of LCK, a tyrosine kinase involved in T-cell receptor signaling, was found in 60% of AA CRCs compared to 5.9% of NHW CRCs. LCK hypermethylation leads to CD4/8 T-cell inactivation and linked to poor outcomes in lung cancer. We observed AA-specific hypermethylation of SSTR1 in 57.2% of AA CRCs compared to 27.6% of NHW CRCs. Somatostasin (SST) suppresses tumor growth by regulating certain factors involved in cell proliferation. Hypermethylation of SSTR1 has been associated with various malignancies including gastric cancer. Lastly, promoter hypermethylation of 3 protocadherin genes was found in 65.1% of AAs compared to 33.1% NHWs. Protocadherins regulate WNT signaling and hypermethylation is associated with poor outcomes in multiple cancers. Taken together, these results show AA-specific CRC methylation changes compared with NHW CRCs. Further work is warranted to investigate the potential functional and clinical implications of these methylation alterations, some of which may represent therapeutic targets and biomarkers. Citation Format: Seeta Rajpara, David N. Buckley, Rosa Xicola, Reger Mikaeel, Mary K. Yagle, Baris Kerimoglu, Curtis Thorne, Dante A. Bellomo, Megha Padi, Xavier Llor, Nathan Ellis, Bodour Salhia. DNA Methylation analysis of African American colorectal cancers reveal race-specific alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7004.