Full Research Project 2: Unusual DNA methylation phenotype in Colorectal Cancer

Project Summary Full Research Project 2 – Colon Cancer Colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer deaths in the United States. CRC can be prevented and treated (at early stages) by routine colonoscopic screening, but lack of early diagnosis is the major cause of fatalities. 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 high risk individuals, such as colonoscopy or endoscopy, are invasive, less popular and subjective. 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 improve CRC diagnostic and outcomes. 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. In the current cycle, we propose to determine the prevalence of OMPs in a larger group of patients from local populations in institutional catchment area in Specific Aim 1A, 156 CRC and 228 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 CRC patients are enriched in Ancestry-informative genetic variants. In Specific Aim 3, we will determine whether environmental factors and social determinants influence the frequency of OMP in most negatively affected individuals. . Develop Foundational Mechanisms for Integration: Our Hunter College/Temple/Fox Chase interdisciplinary team of bench scientists, clinicians and community outreach scientists is in a unique position to reduce impediments that lead to inadequate depiction of the differences in cancer outcomes across all populations in epigenetic research studies. This project addresses data gaps by including local populations in institutional catchment area in the epigenetic studies and by developing quantitative and less invasive screening tests that will potentially enable to augment the uptake of CRC screening and improve colon cancer outcomes across all populations.