Genetic susceptibility markers in surrogate/target tissu

University Of Texas Md Anderson Can Ctr, Houston TX

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Abstract

DESCRIPTION (provided by applicant): In a series of cases with oral cavity cancers (n=300) and oral premalignant lesions (n=100), we propose an integrated molecular epidemiologic approach to correlate genetic susceptibility phenotype and genotype data in lymphocytes, and to extend these findings to biopsies and surgical specimens of premalignant and malignant oral cavity lesions. We will measure functional nucleotide excision repair (NER) capacity using the host cell reactivation assay with plasmids damaged by benzo(a)pyrene, and establish frequencies of select polymorphisms in DNA repair genes implicated in the nucleotide excision repair pathway (ERCC1, XPC, XPD/ERCC2, XPF/ERCC4). We will correlate genotype with functional NER activity. We hypothesize that individuals with "adverse" genotypes of the nucleotide excision repair pathway will exhibit poorer DNA repair capacity. In surgical specimens from the two case groups, we will assess LOH at 3p14 and 3p21, 9p21 and 17p13 and correlate with epidemiologic covariates and constitutional markers of genomic instability (DNA repair capacity, genotypes). Finally, we will identify a subset of 100 patients with oral cavity cancer for whom we will assess BPDE-induced specific chromosomal hotspots (3p21, 3p14) in lymphocyte cultures for comparison with tissue LOH data. We hypothesize that there will be concordance in the severity of sitespecific chromosomal lesions in target and surrogate tissue. The overarching goal of these studies is to determine if the lymphocyte markers that we have already shown to be significant predictors of cancer risk (DNA repair capacity and DNA repair gene polymorphisms) are an adequate reflection of genetic events in the target organ tissue. This finding will have substantial implications for future large-scale population-based molecular epidemiology studies. The long-term application to risk assessment and, therefore, cancer prevention and early detection is considerable.