MOLECULAR EPIDEMIOLOGY OF HUMAN CANCER

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Increasing evidence shows that environmental carcinogens can leave "fingerprints" of genetic damage in the p53 tumor suppressor gene within human tumors, e.g., environmental tobacco smoke and radon produce molecular signatures in lung cancers from nonsmokers. These data suggest that specific carcinogens may be linked directly to individual tumors by telltale mutation profiles. Passive smoking has been linked to lung cancer development by several epidemiologic studies, and the Environmental Protection Agency classified secondhand smoke as a Class A carcinogen in December 1992. This project examines human lung tumor tissues from nonsmokers for genetic evidence linking secondhand smoke exposure to mutations in the p53 tumor suppressor gene. Specific hypotheses include: (i) Frequency of G:C to T:A transversions with a coding strand bias will correlate with passive smoke exposure. (ii) Susceptibility factors including GSTM1 and CYP1A1 genotypes will modulate the frequency of G:C to T:A transversions. A case-control study of lung cancer is being conducted at the University of Maryland. To date, 254 subjects have been accrued. All subjects have received phenotyping for host capacity in carcinogen metabolism. Genotyping of cancer susceptibility genes will be conducted. Germline mutations of BRCA1 and BRCA2 confer high risks of breast cancer, and some kindreds have excess ovarian, colon, and prostate cancers. We tested the hypothesis that germline BRCA1/2 mutations predispose Ashkenazi Jews to prostate cancer. We collected prostate tumor samples from 91 Jewish Ashkenazis in Baltimore. We screened for the BRCA1 185delAG mutation plus the BRCA2 6174delT, 999del5, 8535delAG, and 9433delGT mutations by PCR and SDS-PAGE. Although the individual NCI-UMD carrier frequencies do not differ from population estimates, the 95% confidence intervals of the combined series exceed the point estimate of the previous studies, indicating that germline BRCA1/2 mutations may increase the risk of prostate cancer among Ashkenazi Jews.