Oxidative DNA Damage, DNA Repair and Oral Cancer

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DESCRIPTION (provided by applicant): Cigarette smoking is the major known head and neck cancer risk factor and represents the single leading preventable cause of death in the United States. Tobacco enhances the production of reactive oxygen species (ROS) in cells, resulting in the generation of oxidative lesions in DNA, such as strand breaks and oxidative DNA base lesions. Among various oxidative DNA lesions, 8-hydroxyguanine (8-OH-G) is by far the most abundant. If not sufficiently repaired, 8-OH-G can cause mutation by mispairing with adenine, yielding G:C to T:A transversion upon DNA replication. The human gene responsible for the repair of this specific DNA lesion was recently cloned and named human 8-oxoguanine DNA glycosylase (hOGG1). The hOGG1 gene is implicated in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC) for several reasons. 1) The hOGG1 gene is located at 3p25, a chromosomal region with frequent allelic loss in HNSCC. 2) Yeast with mutations in this gene produce a mutator phenotype with accumulation of G:C to T:A transversions. 3) Studies of p53 mutations in HNSCC-related tumors showed a bias in favor of G:C to T:A transversions, as indeed would be expected if hOGG1 repair function was disabled. 4) The hOGG1 gene is amenable to the proposed study because of availability of its complete genomic DNA sequence, intragenic single nucleotide polymorphism (SNP) sites, and antibodies to the gene product. We hypothesize that hOGG1 inactivation promotes the development of oral SCC and this hypothesis will be tested by the following three specific aims. 1) Determine the frequency of loss of heterozygosity (LOH) in the hOGG1 gene. 2) Characterize the hOGG1 protein expression patterns in normal and neoplastic squamous mucosa. 3) Explore the genetic or epigenetic mechanisms of hOGG1 inactivation by identifying somatic mutations or promoter methylation in the oral SCC cases with evidence of LOH or lack of protein expression of hOGG1. The role of hOGG1 inactivation has never been previously examined in oral SCC. This study will help to determine whether hOGG1 can be used as a genetic marker for early detection, prognostic prediction, and a potential target for gene therapy in oral SCC. By obtaining a K award, the PI will have the opportunity to develop skills for patient- oriented research under the direction of basic and clinical science mentors.