Kaposi sarcoma (KS) is by far the most common malignancy associated with human herpesvirus-8 (HHV-8)/KS-associated herpesvirus (KSHV) infection and ranks among the most common overall childhood cancers in sub-Saharan Africa. Over the past decade, our pediatric HIV malignancy program at the Baylor International Pediatric AIDS Initiative at Texas Children's Hospital/Global HOPE (Hematology-Oncology Pediatric Excellence) Clinical Center of Excellence in Lilongwe, Malawi has cared for over 200 children with KS. Our work has highlighted the clinical characteristics that render childhood KS distinct from adult disease, defined the heterogeneity in disease presentation specific to pediatrics, and established risk-stratified treatment regimens that have improved long-term survival. Long-term complete remission and event-free survival can be achieved, especially in children with lymphadenopathic KS. In stark contrast, patients with advanced visceral or disseminated disease experience high mortality rates despite intensified chemotherapeutic approaches. We have also identified associations between clinical sub-groups and KSHV-mediated mechanisms of KS oncogenesis specific to childhood disease. However, there remains a gap in knowledge concerning the inherent pathogenic mechanisms of KS. The proposed study seeks to define somatic genetic alterations of pediatric KS and determine correlations with clinical and virologic features through analysis of tumor specimens from the largest existing biocohort of childhood KS patients (n=70) from Lilongwe, Malawi. Through improved understanding of the molecular features of pediatric KS, we aim to discover biomarkers and targetable pathways that may inform the development of novel diagnostic, prognostic and therapeutic strategies.