This application is a resubmission in response to the Funding Opportunity Announcement (FOA) identified as PAR-21-271. PROJECT SUMMARY In the US, cancer disproportionately affects many racial/ethnic minority communities, defining significant cancer health disparities (CHDs). Across all racial/ethnic groups, American Indians and Alaskan Natives (AIANs) experience one of the most substantial disparities with the highest comorbidity rates and lowest 5-year survival rates for all major cancer types. CHDs are driven by a combination of biological and social determinants of health, but actionable knowledge of both elements remains severely limited for AIANs. In this K99 proposal, I will address two critical problems that have perpetuated CHDs among American Indians/Alaskan Natives (AIANs): underrepresentation in precision medicine that limits discovery translation and race-level trends for outcomes and SDOH that conceal community diversity critical to effective implementation. Neither issue can be successfully addressed without the involvement and voices of Native communities, who have long been subjected to extractive research practices with little to no return on community health. This proposal centers Native communities living within the UCD Comprehensive Cancer Center catchment area (UCDCCC-CA) in a community-based participatory research (CBPR) framework to develop guidelines for appropriate Native community engagement for biomedical research while assessing community-level biological and social determinants of cancer health and care access. In Aim 1, I will utilize whole exome sequencing data from 300 Hispanic/Latino (HL) gastric cancer samples to identify somatic alterations that are associated with Indigenous American (IA) genetic ancestry at both global and local ancestry levels. These may be applicable to AIANs who also share high IA ancestry. Associated loci will be functionally validated in HL patient-derived organoid models in the R00 phase. In Aim 2, I will administer a validated survey and conducted focus groups interviews to identify key factors that contribute to individual decision-making for participation and biospecimen donation in cancer research among AIANs. In the R00 phase, I will work with UCDCCC-CA Native community stakeholders and my Native community advisory board to translate these findings into Native community engagement guidelines for research. In Aim 3, I will utilize cancer risk and health behavior data from the Aim 2 survey and cancer outcomes and sociodemographic data from the California Cancer Registry to elucidate community-level social determinant of health that drive UCDCCC-CA Native community cancer outcomes. In the R00 phase, I will use these findings to identify areas of intervention in collaboration with community and Native-focused health clinic partners to improve Native community cancer health. This proposal fulfills the mission of the National Institute for Minority Health and Health Disparities to unders...