The focus of Project 2 is to integrate the pre-diagnosis Epstein- Barr virus (EBV) serology in relation to the molecular status of Hodgkin's disease (HD) cases in order to elucidate the interplay of host and viral factors in the pathogenesis of this disease. We will conduct a nested case-control study of incident cases and matched controls from the Army-Navy Serum Repository (ANSR) which contains specimens from over 3 million men and women from the United States uniformed services. We expect a total of 200 cases and 200 controls. Tissue blocks from all cases will be tested for EBV genome status. These data will be evaluated for consistency with three models of HD pathogenesis: 1. The EBV is solely related to EBV-genome positive HD with EBV-genome negative disease due to non-viral causes; 2. HD is a virally induced malignancy with the EBV responsible for EBV- genome positive disease and another unidentified virus(es) linked to EBV-genome negative disease; 3. The EBV plays a crucial early role in the pathogenesis of essentially all HD cases but the genome is selectively lost in some patients. Both case-case and case- control serologic comparisons will be done. We will also evaluate the consistency of pre-diagnosis and post-diagnosis serum samples frog cases. By integrating the, EBV serologic profile preceding diagnosis and molecular data of a large series of cases, we should move forward in describing the natural history of this disease.