Despite notable advances in early diagnosis and local disease control, oral carcinoma remains a significant public health problem worldwide. Over the past thirty years, while the cancer incidence rates have increased among men and women, limited improvement of the cure and five-year survival rates has been achieved through classical multimodal therapeutic approaches, encouraging the development of innovative strategies. The rational development of novel approaches for the prevention, early detection, and effective treatment of oral carcinoma is critically dependent on a better understanding of the molecular and cellular mechanisms specific biomarkers for cancer risk assessment, early detection underlying the tumorigenesis process in the oral cavity. This knowledge will lead to the identification of specific biomarkers for cancer risk assessment, early detection of disease, response to primary or secondary intervention, and prognostic evaluation of the disease. Moreover, the identification of the key biologic pathways in the tumorigenesis process will lead to the development of new, targeted interventional approaches. Molecular cytogenetic analyses of oral cavity tumors have uncovered a number of recurrent genetic events. While a limited number of candidate genes have been identified, little is known about their function during oral tumorigenesis. Chromosome 1lq13 gene amplification is observed in 30-50% of oral cancers and may involve several genes potentially important for creating the malignant phenotype. The goal of this project is to determine the etiology, timing, and functional consequences of chromosome 11ql 3 amplification during the multistep, oral tumorigenesis process. The working hypothesis is that different genetic events associated with oral tumorigenesis interact in a synergistic fashion to drive the accumulation of the functional pathways necessary for malignant evolution. Characterizing the evolving tissue at critical times of genetic alteration will permit a better understanding of the functional consequences of these interactive genetic events in oral malignancy. The following Specific Aims are proposed:
Specific Aim 1 : Determine the frequency and functional consequences of chromosome 1l ql 3 gene amplification during the multistep process.
Specific Aim 2 : Determine the functional significance of cyclin D 1 alterations for oral tumorigenesis.
Specific Aim 3 : Determine the role of EMS 1 alterations during the multistep process The in vivo model system for these studies will be human oral tumor resection specimens exhibiting contiguous histologic evidence of a transition from normal epithelium through premalignant regions to invasive disease. Using in situ approaches (in situ hybridization, microdissection and PCR, and immunohistochemistry), sequential genetic and phenotypic events (e.g., genomic instability, gene amplification, dysregulated proliferation, altered migration) will be characterized during the multistep process. New hypotheses derived from observations in the in vivo model system will be tested in an in vitro, two-dimensional tissue culture model where candidate gene expression can be regulated and its functional consequences characterized spatially and quantitatively in cell outgrowths. The elucidation of the pathways and forces that drive the multistep process in the oral cavity will allow a better understanding of the biological underpinnings of oral cancer development and will lead to the development of new approaches to reduce the morbidity and mortality of oral cancer.
