Human papilloma viruses (HPVs) are involved in the pathogenesis of different types of human cancers, including a subset of squamous cell carcinoma of the head and neck (SCCHN). This proposal involves identification of cellular gene expression profiles in fresh tissues from patients with HPV-positive and HPV-negative SCCHN and premalignant lesions. Since the majority of HPV-associated SCCHN arise in the oropharynx (tonsil and base of tongue), we will specifically analyze tumors from this sub-site. The hypothesis to be tested is that significant changes in gene expression profiles occur during the development of HPV-associated SCCHN, and these profiles are unique to a particular stage of the disease and response to therapy. We will accomplish our goals by using Affymetrix GeneChips representing approximately 22,000 human genes. We will also measure the expression levels of the HPV regulatory E2 gene and the E6 and E7 oncogenes in SCCHN tissues and premalignant lesions. The relationship between viral oncogene expression and cellular gene expression profiles will be investigated. We also plan to carry out serum protein profiling in individuals with HPV-positive and HPV-negative SCCHN, and those with premalignant lesions by SELDI-TOF mass spectrometry to identify specific biomarkers associated with this disease. The proposed studies represent a collaborative effort between investigators with multidisciplinary expertise in areas such as molecular biology, virology, genomics, proteomics, immunology, cancer biology and bioinformatics. Our long-term goals are to get a better understanding of the relationship between oncogenic HPVs and carcinogenesis by comparing the HPV-infected tumors with HPV-negative SCCHN. Our studies will provide important information on cellular pathways altered during tumor progression in both HPV-positive and HPV-negative SCCHN.