Abstract C060: DNA Methylation analysis of African American colorectal cancers reveal race-specific alterations

Abstract

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 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 microsatellite-stable colorectal tumor at the Yale New Health System were included in the study. A pathologist reviewed archival slides, and selected areas from tumor (n=160) and adjacent normal tissue (n=42) were cored. The median age of patients was 59 from 82 females and 78 males. Extracted DNA was bisulfite converted and tested using EPIC arrays. DNA methylation (450K) from NHW CRCs was also analyzed for 217 CRCs and 20 normal tissues obtained from TCGA (median age=70; 114 males, 103 females). Differentially methylated regions (DMRs) with |Db|>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, compared with 18% in gene bodies, 5% in enhancer regions, and 6% in intergenic regions. Next, we performed an additional DMR analysis using overlapping probes from the 450K and EPIC arrays to compare TCGA NHW with Yale AA data. We identified 2290 DMRs between AA CRC and normal tissue compared to 4657 in NHW. Of the 2290 AA DMRs, 1405 (61%) were common with NHW DMRs, 885 (39%) were unique to AAs. There were many overlapping pathways and genes involving metabolic functions, DNA damage response, immune response, and WNT signaling. However, the DMRs impacting these pathways differed between AA and NHW CRCs. Several AA-specific DMRs were associated with immune response and included LCK and GPSM3 genes. Hypermethylation of LCK, a tyrosine kinase involved in T-cell receptor signaling, was found in 60% of AA CRCs compared to 8% of NHW CRCs. LCK hypermethylation leads to CD4/8 T-cell inactivation and is linked to poor outcomes in lung cancer. We also observed AA-specific hypermethylation of GPSM3 in 60% of AA CRCs compared to 18% of NHW CRCs. GPSM3 is associated with CD4/8 T-cell infiltration. Lastly, promoter hypermethylation of 6 protocadherin genes was found in 59% of AAs compared to 20% NHWs. Protocadherins play a role in regulating WNT signaling and hypermethylation has been 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: David N. Buckley, Rosa Xicola, Mikaeel Reger, Mary K. Yagle, Baris Kerimoglu, Curtis Thorne, Dante 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 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C060.