DNA repair, Cell cycle Checkpoints and Apoptosis and Bladder Cancer Risk

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My long-term goal is to become an independent molecular epidemiologist with in-depth training in genetics and advanced statistical methods in order to be able to analyzehigh throughput gene variant data to explore gene- gene and gene-environment interactions in cancer susceptibility. Mycareer development plan includedidatic courses/seminars, meetings with mentors in the areas of human genetics, cancer biology and advanced statistical methods. Myresearch proposal will focus on genetic susceptibility of blader cancer (BC). I propose to capitalize on availabilityof epidemiologicand genentic marker data from an on-going case-control study, "Markers of GeneticSusceptibilityto Bladder Cancer"(R01 CA74880,PI:Xifeng. Wu). The parent study currently include over 2,500,mostly Caucasian,BCcases and controls, matched on sex, age and ethnicity. Mygoal is to identify novel loci that confer bladder cancer susceptibility using state-of-the-art genotyping techology and novel statistical and bioinformaticstools. The Specific Aims are: 1) To enhance my knowledge and skills in genetics and statistics to identify novel genetic loci as susceptibility markers of BC by extending the original45 potential functional SNPs to include additional 2112 tagging SNPs in genes in the DNArepair, cell cycle control and apoptotic pathways in 800 Caucasiancases and 800 Caucasiancontrols using the Illumina Golden Gate Assay; 2) To assess haplotypes and diplotypes as markers of susceptibility; 3) To use bioinformaticstools to assess functional significance of SNPs in the DNArepair, cell cycle control and apoptotic pathways and to correlate genotype data of DNArepair and cell cycle control with functional data derived from phenotypic assays. The secondary aim is to apply hierarchical models to refine risk assessment and to apply novel machine-learning tools to explore any gene-environment and gene-gene interactions influencing BCrisk. My project complements the parent grant in that it: 1) adds tagging SNPs to potential functional SNPs addressed in the parent grant; 2) adds haplotype analyses; 3) proposes novel statistical and bioinformaticsapproaches. RELEVANCE (See instructions): Bladder cancer is a tobacco-related cancer which is the fourth most common cancer in men in U.S. The fact that only a fraction of smokers develop bladder caricer indicating genetic susceptibility to the disease. This study will identify novel genetic markers may be useful as biomarkers to identify high-risk populationsthat could then be targeted for intervention programs.