Hodgkin lymphoma (HL) accounts for ten percent of all lymphomas in the western world and remains a substantial clinical problem. Relapsed and refractory (R/R) HL presents a particularly critical unmet clinical need because approximately 25% of HL patients will be refractory to the standard of care or will relapse while receiving treatment, and the overall survival of R/R HL patients is ~50%. New targeted treatment options and improved risk assessment are needed to improve the therapeutic options for these patients. HL is defined by a rare malignant B cell (Hodgkin-Reed-Sternberg , HRS cells) that occupies a small fraction of the tumor microenvironment. Despite many advances in next generation sequencing technologies, the identification of somatic variants in cancers characterized by rare cell populations remains technically and analytically challenging. These obstacles have resulted in a limited number of studies that have used high throughput genome-wide technologies to characterize the genomic landscape of newly diagnosed HL, and far fewer have attempted to use these technologies to address the genomic landscape of R/R HL. Here, we address this shortfall by asking three questions: 1) Can ultra-deep genome-wide sequencing, paired with analysis and filtering strategies optimized for low VAF variants identify somatic variants driving treatment resistance in R/R HL? 2) Can we use somatic mutation status in a large cohort of newly diagnosed and R/R HL to identify genes that are predictive of response to therapy? 3) Can somatic mutations identified in genomic and/or cell free DNA describe clonal heterogeneity among HRS cells and can cell free DNA serve as biomarker of HL at diagnosis or relapse? This research will be broadly impactful because: 1) it will describe the genomic landscape of R/R HL and will identify biomarkers that are predictive of poor response to treatment; 2) it will begin to address the relationship between clonal architecture in HL, disease outcome, and prognosis; 3) it will further define cfDNA as a suitable target for HL disease monitoring By completing this proposal Dr. Felicia Gomez will gain advanced training in genomics, bioinformatics, lymphoma biology, and cancer biology in general. This proposal takes advantage of the cutting edge genomics and cancer research at Washington University School of Medicine (WUSM). WUSM is an ideal location to complete the experiments and training described in this proposal. Dr. Gomez is a well-trained scholar who is poised to develop a program of research that will be innovative and responsive to the need for diversity in the biomedical workforce. When Dr. Gomez transitions to independence she will continue to focus on cancer genomics and will broaden her research to address the interactions between somatic and germline variation and how this interaction affects the development and progression of lymphoma and other malignancies.