Full Research Project 2: Changes in DNA methylation phenotype in CRC associated with racial disparities

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Project Summary Full Research Project 2 – Colon Cancer Changes in DNA methylation phenotype in CRC associated with racial disparities TUFCCC: Carmen Sapienza, PhD (Co-Leader) and Jayashri Ghosh, PhD (Co-Leader, ESI) HC: Frida E. Kleiman, PhD (Co-Leader) Colorectal cancer (CRC) incidence and mortality rates are disproportionately higher in African Americans (AA) compared to Caucasian Americans (CA). Current non-invasive screening tools, such as fecal occult blood tests (FOBT) or fecal DNA markers, detect cancer after it occurs. More effective tools for prevention and treatment of higher risk individuals, such as colonoscopy or endoscopy, are invasive, less popular and subjective, and current uptake of these screening tools is lower among AA compared to CA. Therefore, identification of early and objective biomarkers that distinguish normal colon mucosa of individuals at high risk for CRC from individuals at low risk might decrease racial disparities in CRC. In our previous U54 Pilot project (Cycle 1), we have identified a subgroup of patients having highly disrupted epigenomes displaying abnormal DNA methylation patterns in their normal mucosa, identified as “Outlier Methylation Phenotype” (OMP). We have been able to significantly associate this phenotype with CRC patients over healthy controls. Furthermore, AA CRC patients appear more than twice as likely as CA patients to have OMP. In the current cycle, we propose to determine the prevalence of OMPs in a larger group of patients in Specific Aim 1A, both AA (150 CRC and 200 controls) and CA (150 CRC and 200 Controls). In Specific Aim 1B, we will elucidate biological mechanisms for the contribution of OMP to CRC tumorigenesis using patient derived organoids (PDO). In Specific Aim 2, we will also determine whether OMP - affected genes in AA patients are enriched in Black/Ancestry-informative genetic variants. In Specific Aim 3, we will determine whether environmental factors and social determinants influence the frequency of OMP in AA groups. Break Systemic Barriers to Inclusion: Our Hunter College/Temple/Fox Chase interdisciplinary team of bench scientists, clinicians and community outreach scientists is in a unique position to reduce systemic barriers that lead to underrepresentation of the AA population in epigenetic research studies. This project addresses data gaps by including AAs in the epigenetic studies and by developing quantitative and less invasive screening tests that will potentially enable AAs to increase the uptake of CRC screening, and reduce colon cancer disparities.