MARKERS OF SUSCEPTIBILITY AS PREDICTORS OF BLADDER CANCER RECURRENCEWe plan to build upon the epidemiologic and genetic findings and the existing specimen and data repository fromthe initial SPORE project and our funded research to evaluate predictors of bladder cancer (BC) recurrence in 800patients with superficial BC. We have previously identified several promising markers in pathways for tobaccocarcinogen activation/detoxification and DMA damage/repair. Now we propose to extend our candidate geneapproach to a pathway-based approach to systematically examine the joint influence of genetic polymorphisms inspecific pathways on clinical outcome; to extend our panel from metabolism and DMA damage/repair pathways toinflammation, oxidative stress, and the TRAIL-induced apoptosis pathways; to integrate clinical and epidemiologicdata with the genetic data to build a quantitative risk assessment model for BC recurrence; to link our research toan ongoing BCG clinical trial on superficial BC; and finally to explore functional significance of the SNPs.
Our specific aims are as follows: (1). 1a. Construct a well-characterized cohort of 800 patients with superficial BC; 1b.Assess frequencies of genetic predisposition markers in all 800 cases including SNPs in genes that are involvedin inflammatory processes, oxidative stress, and TRAIL induced apoptosis. Our hypothesis is thatpolymorphisms in these genes are associated with risk of BC recurrence, and may also have effects onBCG treatment response in patients with superficial BC. 1c. Build up risk assessment model for BCrecurrence. We will integrate clinical and epidemiologic data with the genetic data from the studies describedabove as well as from the initial grants to build a quantitative risk assessment model for BC recurrence. Geneticvariations on metabolic enzyme genes, microenvironment genes, and DNA repair genes will be available from ourother funding sources to be incorporated into the model. (2). Assess determinants of BCG treatment response in200 patients with superficial BC enrolled in a clinical trial. We will measure protein levels of IL-2, IL-8, and TRAILin voided urine specimens. We will correlate these protein levels as well as SNPs in pathways relevant to the theaction of BCG (especially genes involved in inflammation, oxidative stress, and TRAIL apoptosis pathways withrecurrence rates. Our hypothesis is that specific genotypes in genes related to the mechanism of BCGaction may negatively affect the treatment response of patients with BC to this therapy. As a secondaryaim, we will use experimental approaches and/or computational approaches to verify or discover the functionalimpact of promising polymorphisms. Our hypothesis is that SNPs associated with bladder cancer recurrencealter the function of their genes. The ability to rapidly screen individuals for BC recurrence risk using minimallyinvasive procedures (blood and urine samples) has immense clinical value. These markers will be useful foridentifying patient subgroups at high risk for recurrence who should undergo more intensive screening. Markers oftreatment response could be used to design individualized treatment plans.
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