Head and Neck cancers (HNC) are the sixth most common cancer in the world, and therefore are a major public health concern. It is now well- established that cancer is a genetic disease at the cellular level. Genetic alterations include the activation of oncogenes and inactivation of tumor suppressor genes. Although substantial progress has been made, still relatively little is known about the genetic mechanisms involved in initiation, progression, and recurrence of these cancers. It is now well accepted that epigenetic alterations (DNA methylation) as well as genetic changes are important for the development of cancer. The importance of DNA methylation in progression of HNCs is not completely understood. To gain a better understanding of the genetic and epigenetic events associated with these events in head and neck squamous cell carcinomas (HNSCC), we propose to identify novel oncogenes and candidate tumor suppressor genes. Our hypothesis is that tumorigenesis of HNSCC is associated with epigenetic changes e.g. promoter methylation, which results in specific changes at the RNA level. We are planning to use the Restriction Landmark Genomic Scanning (RLGS) method which is uniquely suited to identify altered DNA methylation patterns as well as DNA amplification. The goals are: (1) to use RLGS to identify novel amplified sequences and tumor suppressor candidate regions based on altered DNA methylation pattern; (2) the construction of an AscI-EcoRV arrayed library to facilitate the cloning. (3) The cloning of candidate cancer genes will focus on those areas that are altered at high frequency in the tumors. Candidate oncogenes will be identified in chromosomal regions with high incidences of LOH and/pr DNA methylation. (4) The final goal is the establishment of suitable diagnostic biomarkers, which can be used for rapid identification of HNSCC-specific alterations.