This K22 application is to support the scholarly training and career development of Dr. Xiaofeng Charles Zhou to become an independent investigator in head and neck cancer research. This application details the strengths and uniqueness of this proposal pertaining to the candidate, the mentor, the career development plan, the environment and the research plan. The proposed research is to test the hypothesis that there are genomic determinants that distinguish progressing from non-progressing oral precancers. The overall risk of malignant transformation of all grades of oral precancers is approximately 18%. It is impossible to predict progressiveness of any one lesion based on conventional clinical and histological features. Genomic-based new classifications are essential to distinguish the progressing from non-progressing oral precancers. The proposed research aims to determine genome-wide differential allelic imbalance (LOH) profiles for progressing and non-progressing oral precancers. Specific Aim 1 is to establish and optimize a series of innovative emerging genomic tools, to be used consecutively for the application on oral precancers in vivo. This will be accomplished during the Scholar Development Phase (2 years). Specific Aim 2, to be performed in the Faculty Transition Phase, is to determine the genome wide LOH profiles in progressing and non-progressing oral precancers and generate molecular classification for the prediction of oral precancer progression. Specific Aim 3 is to identify candidate genes for oral precancer progression in the identified LOH regions. Functional and biological tests are in place to evaluate the functional contribution of candidate genes to the tumor progression process. A career development plan is in place to prepare the candidate for translational head and neck cancer research. Defined and evaluative milestones are in place to assess the scientific progress of the candidate, particularly during transition to the Faculty Transition Phase. In addition to the research training, the candidate will receive didactic training in bioethics and responsible conduct of research, oral pathology, biostatistics, and grant writing. The outcome of this award will be a well prepared and competitive young scientist committed to a career in translational head and neck cancer research.