PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the 1st and 2nd leading cause of cancer death in men and women in Puerto Rico and the in U.S., respectively. Although CRC incidence and mortality trends have been declining, overall, the incidence and mortality in individuals younger than 50 years (early-onset CRC) have been rising consistently, and the incidence of this CRC subtype is projected increase by more than 140% by 2030. Disparities in CRC incidence and survival have been well documented in racial/ethnic groups in the mainland U.S. However, aggregating heterogeneous populations, such as Hispanics, conceals the significant variability that exists within subgroups in terms of CRC incidence and mortality. CRC represents a malignancy with documented disparities when comparing Hispanics living in Puerto Rico (HPR) with racial/ethnic groups living in the mainland U.S., yet very little is known regarding early-onset epidemiological trends or the pre-disposing risk factors in this Hispanic subpopulation. Moreover, the etiology of early-onset CRC and how germline genetic variation may contribute to early-onset CRC health disparities remain poorly understood. With this in mind, the main goal of the proposed study is to: (Aim 1) characterize early-onset CRC sociodemographic and epidemiological trends in Puerto Rico for the first time; (Aim 2) identify germline genetic variants that predispose individuals to develop CRC before the age of 50; and (Aim 3) establish an early-onset CRC biospecimen (blood, normal mucosa and tumor tissue, and stool) and organoid biobank. Our central hypothesis is that we will observe disparities in early-onset CRC incidence and survival in HPR compared to other racial/ethnic groups in the mainland U.S. and that we will identify novel, unique variants associated with early-onset CRC in HPR. The successful completion of the proposed specific aims will put the principal investigator (PI) in a unique and advantageous position by allowing her to develop skills in molecular epidemiology, germline genetic analysis, and generation of CRC organoids, and in parallel will provide data that will be used as preliminary data for a future R01 submission examining novel risk-stratification, prevention, and/or treatment strategies in year 2. This study will significantly advance the field by providing insight into the factors contributing to the early-onset CRC burden among HPR, the genes and pathways that may contribute to colorectal carcinogenesis in young individuals (<50 years), and in establishing the first early-onset CRC biospecimen and organoid biobank in the Caribbean derived from HPR that will enable for future studies aimed at examining the early-onset CRC risk factors and pathogenic mechanisms, and will make comparisons to other racial/ethnic groups feasible. All of which, will provide the PI with the foundation to pursue new research avenues in her independent research program focused on elucidating the factors contributing...