Overall Summary/Abstract Disparities in colorectal cancer (CRC) incidence and mortality are appreciable and continue to persist in the United States. These disparities are particularly pronounced among the Alaska Native and African American populations. Alaska Native people have among the highest incidence and mortality rates of CRC in the world. The etiology of CRC is multi-dimensional and is influenced by diet, lifestyle factors, medical history, gut microbiome and genetics. However, our understanding of the biological bases for these disparities, particularly as they pertain to mortality, is limited. Three primary gaps in our knowledge are: 1. Our understanding of differences and similarities in the molecular and microbial characteristics of colorectal tumors by race/ethnicity, 2. Our ability to identify patients from different racial/ethnic groups who have elevated risks of CRC mortality and who could benefit from more frequent surveillance and/or additional treatment modalities; and 3. Discovery and validation of novel biological characteristics related to risk of CRC mortality that can serve as potential therapeutic targets. Given the distinct epidemiology and etiologies of CRC across racial/ethnic populations, we hypothesize that important biological differences are present across different races/ethnicities and that these differences will have clinical utility with respect to both distinguishing indolent vs. lethal CRC and informing the development of novel therapeutic strategies. Addressing these gaps could directly reduce persistent CRC disparities. Our Translational Research Program on Colorectal Cancer Disparities (TRPCD) is specifically developed to address these gaps through new collaborations and leveraging existing clinical and epidemiological data and tumor biospecimens from diverse patient populations. This program will include data and biospecimens from 840 CRC patients with equal numbers coming from Alaska Natives, African Americans, Hispanics/Latinos and non-Hispanic whites. Our two primary goals are: 1. Build the infrastructure needed to support a highly competitive P50 SPORE proposal through the development of an Administrative Core and Biospecimen and Pathology Core; and 2. Advance our capacity to conduct translational cancer disparities research through executing two high-quality Full Projects and establishing a robust Developmental Research Program. Full Project 1 will conduct transcriptomic analyses on the 840 patient tumors to identify novel tumor- tissue based predictors of lethal CRC by race/ethnicity. Full Project 2 will study the gut microbiome in the same 840 patient tumors and assess the impact of the gut microbiome on the tumor microenvironment and CRC mortality overall and by race/ethnicity. Both Projects have the potential to directly impact the gaps described above with respect to identifying clinically actionable racial/ethnic differences, improving the identification of patients at risk of lethal CRC, and...