Racial Disparities and Colorectal DNA Methylation- Driven Gene Expression

ABSTRACT Racial disparities in colorectal cancer (CRC) are widening. There are well-documented racial differences in anatomical location distribution of CRC. African Americans (AAs) are more likely to develop right side CRC and diagnosed at younger age than European Americans (EAs). The mechanisms underlying these

observed racial disparities and the relationship to sidedness remain poorly understood. DNA methylation is a key epigenetic regulator of transcription. Epigenetic alterations result in accelerated aging and changes in gene expression, which are believed to drive colon tumorigenesis. In a recent study of colorectal biopsies from 128

patients, we discovered that human colon exhibits remarkable racial and side differences in DNA methylation and epigenetic aging. The right colon of AAs shows enrichment of hypermethylated differentially-methylated positions (DMPs) and accelerated epigenetic aging whereas the right colon of EAs shows decelerated aging as

compared to left colon. Our analysis of rectal DNA methylation shows similar racial differences. We further show that in patient-derived normal colon organoids, response to environmental exposures is colon side specific and impacts global gene expression, further implying differing biology between right vs left colon, and

vs rectum. These novel observations led to our central hypothesis that there are distinct epigenetic and transcriptomic perturbations underlying racial disparities in the development of site-specific colorectal neoplasia. We here propose to perform RNA-sequencing of 384 individual-matched triplet colorectal biopsies

(right vs. left colon vs. rectum) from the 128 patients in our hands. In combination with DNA methylation data already generated on these patients, we will use a supervised approach to integrate omics data on the transcriptome and methylome, and to identify DNA methylation-driven gene expression signatures that may

provide biological insight of the racial disparities and colorectal site differences observed. In Aim 1, we will identify within-individual site-specific DNA methylation-associated gene expression signatures across colorectum locations (right vs left colon vs rectum). In Aim 2, we will identify cross-individual racial differences

in site-specific DNA methylation-associated gene expression signatures. In Aim 3, we will identify gene expression signatures associated with site- and race-specific epigenetic age acceleration. Our study will provide novel insight of the epigenetic and transcriptomic underpinnings of racial disparities in risk of site

specific CRC, and guide the development of prevention strategies to reduce racial disparities by targeting critical epigenetic/transcriptomic pathways linked to colon carcinogenesis.