Colorectal cancer (CRC) incidence and mortality rates vary significantly across population groups and these differences extend beyond access to screening and health care suggesting underlying contributors to disease etiology, progression, and response to treatment. By studying population groups with different cancer rates, we enhance our ability to identify the molecular characteristics and contributing factors driving these differences. Despite advances in biotechnology, tools for analyzing tumor and host molecular genetics and genomic biology have not been fully utilized to address these differences. Our team has the expertise to use cutting-edge technologies to drive innovative translational cancer research aimed at developing novel prevention, early detection, diagnosis, and treatment approaches. To achieve our goal of reducing differences in CRC incidence and mortality between population groups, we propose the following specific aims: Aim 1: Improve risk stratified screening and early detection of CRC across population groups by developing risk prediction models that perform similarly well across population groups. Aim 2: Reduce differences in CRC-specific mortality across population groups by discovering and validating novel molecular and biological changes related to risk of lethal CRC and response to treatment in CRC patients that can guide surveillance and treatment selection for CRC survivors. Aim 3: Discover novel therapeutic targets for CRC across population groups with varying mortality rates and test potential clinical interventions aimed at reducing CRC mortality by advancing our understanding of differences and similarities in the genetic, molecular, and microbial characteristics of CRC in different populations and testing the effectiveness of novel interventions in CRC clinical trials. During the P20 SPORE phase we assembled a robust biorepository and clinical data from a large CRC patient population and through our long-term leadership in genetic epidemiology we have access to the world’s largest CRC germline genetic data set from population groups with different incidence and mortality rates. Utilizing these resources, our program will conduct four impactful projects supported by three centralized cores - a) leadership and administration, b) biospecimens, pathology and molecular technologies, and c) biostatistics and bioinformatics. Our Career Enhancement and Developmental Research Programs will cultivate new investigators and novel translational research projects. Through this integrated effort we aim to build a lasting translational research program to understand and reduce differences in CRC incidence, mortality and overall disease burden.