One of our goals is to characterize the patterns of genetic damage caused by different environmental exposures in key genes which presumably initiate carcinogenesis. Our studies have focused on two model human tumors with strong environmental determinants: non-small cell lung cancer and transitional cell carcinoma of the bladder. In lung cancer we are assaying for K-ras mutational activation at codons 12, 13, and 61, and deactivation of the tumor suppressor gene p53 at exons 4-9 in a large series of tumors from patients with different etiologic exposures. We are currently completing assays of tumors from uranium miners from the Colorado Plateau with heavy radon exposure. In addition we have collected tumors from people with heavy exposure to asbestos, nickel, and tobacco smoke and we will contrast the patterns of DNA damage found in these patients with that found in radon-induced lung tumors. In bladder cancer we have completed assays for H-ras activation in a series of tumors from people exposed to arylamines, cyclophosphamide, or tobacco smoke and are completing assays on p53. In all cases we have been using PCR on formalin-fixed paraffin- embedded surgical blocks, followed by either oligonucleotide hybridization or SSCP with direct sequencing of positive samples. We have just completed enrollment in a 400 person case-control study on the genetic and environmental determinants of bladder cancer. A major goal of this study is to identify allelic variants of key candidate genes which increase a person's susceptibility to environmentally-induced bladder cancer. We have been genotyping people for two classes of putative susceptibility genes: genes which are responsible for carcinogen metabolism such as N-acetyltransferase, glutathione-S-transferase, and various p450s, and polymorphic proto-oncogenes whose allelic variants may affect susceptibility.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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