MOLECULAR EPIDEMIOLOGY OF HEAD AND NECK CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Smoking and alcohol consumption are the dominant risk factors for head and neck (HN) cancer but little is known about the genetic factors defining individual susceptibility. This study is designed to search for risk factors among phenotypic and genotypic markers of response to genotoxic stress. Comet assay and mutagen sensitivity evaluate response to DNA damage (e.g. bleomycin exposure) in short-term cultured human lymphocytes. Mutagen sensitivity was previously used as a marker of HN cancer risk and comet assay is an increasingly popular measure of DNA damage and repair that has yet to be tested in HN cancer. High DNA damage (tail moment in comet assay or chromaid breads in mutagen sensitivity) and low rate of DNA repair correlate with increased risk of certain cancers. This study will evaluate comet assay as a measure of HN cancer risk. Programed cell death (apoptosis) is one way to eliminate cells that did not repair correctly DNA damage. We hypothesize that low apoptotic response to bleomycin exposure in the short-term cultured lymphocytes is indicative of increased cancer risk. In addition we will examine how these phenotypic measures in white blood cells correlate with mutations of the p53 tumor suppressor gene in the tumor issue. The p53 gene guards cells from carcinogenic changes and is often mutated in HN cancer. It is expected that insufficient response to genotoxic stress correlates with high frequency of some p53 mutations. Genetic variants with decreased DNA repair capacity were previously described in both base excision repair (APE1, XRCC1), nucleotide excision repair (XPD), and recombinational repair (XRCC3) pathways. Correlation of these genetic variants with DNA damage/repair (comet assay), apoptosis, and p53 mutations in HN tumor tissue will be examined. Hypothesis: Our hypothesis is that head and neck cancer risk is related to inter individual variability in the response to genotoxic stress. Specific Aims: This study has two major goals. Aim 1 - Establish a data and tissue repository for studies of HN cancer. Aim2 - Use the repository to determine whether decreased ability to respond to DNA damage correlates with increased HN cancer risk. Study Design: The case-control study will evaluate 100 HN cancer cases and 100 non-cancer controls matched on age, gender, race and smoking status. Epidemiological data, clinical data, and samples of blood, buccal cells, saliva, urine, and tumor tissue will be obtained and examined for markers of genetic susceptibility to HN cancer. White blood cells will be cultured for a short term to test response to DNA damage (comet assay, mutagen sensitivity and apoptosis) and DNA and other biomolecules will be extracted from the various specimen to evaluate genetic variants in DNA repair genes, mutations in the p53 tumor suppressor gens, and other markers of cancer susceptibility. Significance: This pilot study is expected to fill important gaps in our understanding of HN cancer etiology, identify genetic modifiers of HN cancer risk, produce new hypotheses to focus HN cancer prevention, and help design better cancer prevention strategies.