Gene-environment interactions and tobacco-related human cancers are both longstanding areas of research in our molecular epidemiology project and extraordinary opportunities in the NCI Bypass budget. The challenging goal of molecular epidemiology is to identify individuals at a high cancer risk by quantitative assessment of carcinogen exposure and genetic analysis of host susceptibility factors. The molecular archaeology of the mutation spectra of tumor suppressor genes generates hypotheses concerning the etiology and molecular pathogenesis of human cancer. The spectrum of somatic mutations in the p53 gene implicates (a) environmental carcinogens, e.g., sunlight, aflatoxin B1, and tobacco smoke, and (b) endogenous agents, e.g., oxyradicals, and processes, e.g., errors occurring during DNA repair and replication, in the etiology of human cancer. To further investigate the role of codon 249 p53 mutations in hepatocellular carcinogenesis, we have both continued our longstanding collaboration with Professor Sun and assessed the separate and combined effects of hepatitis B virus (HBV), hepatitis C virus (HCV), and aflatoxin B1 in causing hepatocellular carcinoma (HCC) in Qidong, China. A consecutive series of 181 pathologic-diagnosed HCC cases were studied for hepatitis B surface antigen (HbsAg), anti-HBc, HBV X gene sequence, anti-HCV, the 249ser-p53 mutation, and chronic hepatitis pathology. The 249ser-p53 mutation was found in 54% of HCC cases and in all seven cases with tissue for analysis from the hepatitis cohort but in none of 42 matched cases from Beijing. The estimated cumulative dose of aflatoxin B1 in these seven cases ranged from 0.13 to 0.49 mg/kg. Follow-up data through 13.3 years on a cohort of 145 men with chronic HBV hepatitis showed that the relative risk from aflatoxin B1 exposure was 3.5 (1.5-8.1). A similar relative risk was found using 249ser-p53 mutation as a marker for aflatoxin B1 exposure. In conclusion, HBV hepatitis is ubiquitous in Qidong HCC cases, whereas HCV contributes little to its risk. The 249ser-p53 mutation appears to result from coexposure to aflatoxin B1 and HBV infection. Even modest levels of aflatoxin B1 exposure tripled the risk of HCC in HBV-infected men. We have continued our studies of the molecular epidemiology of human lung cancer risk. We are investigating the gene-environment interactions in tobacco-related lung cancer using case-control and case-case strategies to examine potential gender and racial differences and lung cancer risk. A unique aspect of our study is the matching of lung cancer cases to both hospital and population controls. Examples of recent results include (a) confirmation and extension of the studies indicating that the mutagen sensitivity assays predict individuals at an increased risk of lung cancers; (b) Codon 312 XPD polymorphism significantly correlates with a lung cancer risk, and modulates apoptosis and is the first known functional polymorphism in an apoptotic gene; (c) p53 mutations are a common and early event in lung cancers from ex-smokers; (d) women may be more sensitive than men to tobacco smoke-induced lung cancer, based on the p53 mutation spectra of their lung cancers and our previous results indicating that never-smoking women who are exposed to environmental tobacco smoke and develop lung cancer, are a genetically susceptible population, e.g., GSTM1 deficient; and (e) when compared with Caucasians, African-Americans with lung cancer have an attenuated G2/M cell cycle checkpoint.
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