The objective of this proposal is to perform comprehensive virologic and focused epidemiologic and molecular pathogenesis studies to evaluate the hypothesis that a subset of head and neck squamous cell carcinomas (HNSCC-defined as SCC of the oral cavity, the pharynx and the larynx for this proposal) is etiologically linked to infections with human papillomaviruses (HPVs). In the USA, each year, there are about 41,000 cancer cases and about 12,00 deaths, due to HNSCC. Alcohol and tobacco use are the best recognized risk factors of HNSCC. Preliminary data suggest that, as compared to HPV-negative HNSCC, HPV- associated HNSCC (about 24 percent of all HNSCC) occur largely in the oropharynx and are less related to history of tobacco and alcohol use and to p53 mutations. The specific aims of the proposed studies are: (i) to define the site distribution of HPV- associated HNSCC, identify the HPV types involved and characterize the virus-cell relationships in HPV-positive tumors in terms of HPV copy numbers per cell, HPV transcripts, localization of the viral genome to tumor cell nuclei, viral integration into cellular DNA, and site of viral integration on the cellular chromosomes, and to compare cases at different sites for their serologic profiles against HPV-16 oncoproteins E6 and E7 and HPV-16 L1 protein; (ii) to describe the molecular and pathologic features of HPV-related tumor progression; and to (iii) to examine the clinical and epidemiologic correlates of HPV-associated HNSCC, especially with respect to survival and to exposure to risk factors relating to alcohol use, tobacco use and sexual activity. It is anticipate that about 1,300 cases of HNSCC attending clinics at Johns Hopkins will be investigated. If HPV etiology is established for a subset of HNSCC, patients with these tumors may benefit from HPV-specific immunotherapies which are being evaluated for the treatment of invasive cervical cancer.