Abstract B082: Interrogating the mechanistic link between neighborhood disadvantage colorectal cancer risk through DNA methylation analysis of African American colorectum
Authors: Devall Matthew , Sun Xiangqing , Eaton Stephen , Yoshida Cynthia , Venkatesh Samyukta , Cooper Gregory , Willis Joseph , Weisenberger Daniel , Casey Graham , Li Li 
Published: December 2023

Abstract
Environmental and social factors account for approximately 65% of colorectal cancer (CRC) risk. Identifying mechanisms associated with CRC risk may provide crucial insight for future drug targeting, as well as prevention and screening strategies. The Neighborhood Disadvantage Index (NDI) is a composite score of 17 social and environmental measures that has been shown to be associated with poorer health outcomes independently of an individual’s own socioeconomic status. While African Americans (AAs) are more likely to live in areas of high NDI, both non-Hispanic Whites and AAs living in areas of high NDI experience increased stress and poorer health. Recently, increased NDI scores have also been positively associated with CRC risk. The mechanisms through which these social factors influence disease risk are yet to be elucidated. DNA methylation represents one epigenetic marker that exists at the interplay between environment and disease risk. Here, we hypothesize that an analysis of NDI in an at-risk population for CRC will reveal DNA methylation differences relevant to disease. We performed genome-wide DNA methylation analysis of triple-matched, normal right and left colon, and rectal biopsies of 72 African Americans using the Illumina Infinium MethylationEPIC kit. After preprocessing of individual probes and samples, we generated a mixed-effects model to define differentially methylated regions (DMRs) that were consistently associated with NDI across all colorectal locations using DMRcate. The duplicateCorrelation function of Limma was used to account for repeated measures through addition of a random intercept. We identified 810 differentially methylated regions (DMRs) associated with NDI. Through gene-set enrichment analysis, we found that these DMRs were associated with CRC risk processes such as cell morphogenesis (FDR= 7.33E-05), development (FDR=1.18E-04) and growth (FDR=1.17E-02). Secondary analysis of five publicly available datasets revealed a subset of 17 that overlapped DMRs identified in all CRC tumor versus normal adjacent tissue analyses. To map DMRs to likely gene expression targets, further analysis was carried out in two, publicly available CRC tumor datasets. Our analysis found that of the 17 targets, eight were differentially expressed in TCGA-COAD with four of these also being differentially expressed in TCGA-READ. This included CAP-Gly domain containing linker protein family member 4 (CLIP4), which was reduced in TCGA-COAD (FDR=1.29E-28) and TCGA-READ (FDR=8.52E-08). DNA hypermethylation of chr2:29337946-29338121, which corresponded to CLIP4, was associated with increasing NDI in our analysis (FDR=0.040). Our study provides the first empirical evidence supporting DNA methylation as a plausible mechanism through which neighborhood socioeconomic disadvantage impacts colon carcinogenesis and drives disproportionately high risk of CRC among African Americans. Specifically, our findings indicate that epigenetic dysregulation of CLIP4 represents one potential marker of NDI-related disease risk.
Citation Format: Matthew Devall, Xiangqing Sun, Stephen Eaton, Cynthia Yoshida, Samyukta Venkatesh, Gregory Cooper, Joseph Willis, Daniel Weisenberger, Graham Casey, Li Li. Interrogating the mechanistic link between neighborhood disadvantage colorectal cancer risk through DNA methylation analysis of African American colorectum [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 B082.