PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-22-057. A better understanding of lymphoma biology has aided in predicting therapy responses and outcomes; however, this cannot entirely explain differences in vulnerable populations. In Latin America (LATAM), lymphotropic viruses (i.e., HTLV-1, EBV) are a common cause of aggressive non-Hodgkin lymphoma (NHL) subtypes and are associated to poor outcomes. The Lymphoma Epidemiology of Outcomes (LEO) cohort study is the largest prospective cohort of NHL survivors in the world. However, only few patients with virally-driven NHL have been enrolled, therefore, limiting the advancement on the knowledge of these rare but fatal diseases. Both EBV- and HTLV-1-associated lymphomas disproportionately affect racial/ethnic underserved populations in LATAM and the U.S., with advancements in the field being precluded by the low numbers of cases seen in the U.S. The overall goals of this supplemental application are to directly extent our ongoing research by expanding the number of NHL subtypes currently registered; improve and develop population-specific prognostic models; advance the current knowledge on rare lymphomas by directly studying NHL subtypes prevalent in LATAM; expand the racial/ethnic diversity of NHL research by recruiting a large number of Hispanic and Native Indigenous patients; and introduce immunogenomics to the study of NHL in LATAM. In this proposal, we aim to establish a partnership between the LEO cohort study and the Latin American Group of Lymphoproliferative Disorders (GELL group). Considering the award period for this supplemental grant, the estimated number of virally-driven NHL subtypes seen per center, and our prior experience collaborating with these centers, we propose to work with two cancer hospitals in Lima, Peru, the Hospital Edgardo Rebagliati and the Instituto Nacional de Enfermedades Neoplasicas (INEN), the two largest cancer hospitals in Peru. Over the next year we propose to: aim 1, develop a clinicopathological database to capture data of 80 HTLV-1/ATLL and 80 EBV+ DLBCL, NOS patients followed for long-term prognosis and survivorship; aim 2, build the resource to investigate the tumor mutational burden and gene expression signature of these viral-associated NHL using DNA and RNA sequencing; and aim 3, develop novel prognostication models by examining the relative contribution of the different clinical variables and genomic data on lymphoma outcomes using principal component and machine learning approach. Drs. Flowers and Malpica have additional resources to perform sequencing for aim 2. This approach will enhance the current knowledge of virally-driven aggressive NHL subtypes and dramatically expand the number of NHL patients characterized with clinical data and genomics beyond LEO. In conclusion, this proposal addresses an exceptional opportunity to research these unique entities in a co...