Our objective is to address the fundamental question concerning the extent to which genetic background modulates human susceptibility to head and neck squamous cell carcinoma (SCCHN). Interindividual and interethnic differences in tobacco carcinogen metabolism are considered to be major contributors to variations observed in disease susceptibility. In addition to variability in activation and detoxification pathways of mutagenic agents, variability in the capacity to repair smoking induced DNA damage is likely to represent another major family of susceptibility biomarkers. The nucleotide excision repair (NER) system is important in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this pathway and mutations in the XPD gene, including the common A35931C (Lys751 Gln) variant allele result in reduced repair capacity. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. The CCND1 G870A polymorphism has been reported to enhance alternate splicing and increase cyclin D1 protein half-life; consequently subjects with the variant allele may have increased susceptibility to increased cell proliferation and the promotion of genetic instability by the bypass of the G1/S checkpoint of the cell cycle control mechanism. We propose to assess the effect of genetic polymorphisms in the XPD and CCND1 genes on susceptibility to HNSCC in order to further refine the HNSCC risk assessment model for individuals with smoking and/or alcohol consumption. We plan to extend our initial observations of an association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1870A variant allele and XPD Gln allele (10.4, 95%CI 5.3-20.4). In specific aim 1, we will validate these results in a series of matched SCCHN cases (N=750) and controls (N=1000). Specific aim 2 will evaluate whether these CCND1 and/or XPD genetic polymorphisms are associated with elevated risk of recurrence or development of a second primary tumor. In specific aim 3, we propose to determine the correlation between CCND1 and XPD polymorphisms in peripheral blood mononuclear cells (PBMC) and, genetic alterations in SCCHN tissues.