Integrative molecular epidemiology: From risk assessment to outcome prediction

Proc Amer Assoc Cancer Res, Volume 46, 2005 SY25-1 Introduction: Molecular epidemiology plays an increasingly prominent role in risk assessment and in identifying genetically high-risk subgroups who might benefit disproportionately from intensive screening or chemoprevention interventions. Molecular epidemiology is also integral to pharmacogenetic research, for construction of genetic profiles that could be used to individualize therapy and to understand the functional consequences of chemoprevention, chemotherapy or radiotherapy response. A unifying premise to these approaches is that the same genes that are implicated in cancer risk, are also involved in the propensity to carcinogenic exposure, risk of carcinogenesis, and prediction of patient outcome. We will select a few representative examples relative to lung cancer to illustrate our theme. Nicotine Addiction: There is compelling evidence for a genetic component to smoking initiation, nicotine dependence and persistent smoking. The intersection of the genetics of exposure (nicotine addiction) and risk (lung cancer) i.e. biobehavioral research, holds promise for greater understanding of the biologic basis of nicotine addiction, and for the development of targeted interventions. CYP2A6, is the hepatic enzyme responsible for metabolism of 70% to 80% of nicotine to its inactive metabolite, cotinine. The same gene is also responsible for metabolic activation of the tobacco-specific nitrosamine, NNK, by α-hydroxylation leading to the formation of DNA methyl adducts. There is substantial interindividual variation in CYP2A6 activity. High activity of the encoded enzyme would result both in increased risk of tobacco addiction and increased activation of NNK to its ultimate carcinogen, thereby increasing risk for lung cancer in smokers. DNA repair: DNA repair may be considered a double-edged sword. Nucleotide excision repair removes bulky adducts induced both by benzo[a]pyrene in tobacco and by platinum chemotherapy. Suboptimal DNA repair capacity is an independent risk factor for cancer, but has also been shown to be associated with improved response to chemotherapy (due to decreased removal of tissue platinum adducts). XPA, is one of seven genetic complementation groups that encode for proteins involved in the nucleotide excision repair. A polymorphism in the 5’ non-coding region may modulate gene expression through transcriptional and post-transcriptional control mechanisms. This variant genotype appears to be associated with a proficient repair phenotype, a lower lung cancer risk, but also a predictor of poorer outcome in patients treated with platinum-based chemotherapy. Detoxification of carcinogens and of platinum compounds by conjugation with glutathione or GSH is catalyzed by the multi-gene family of glutathione S -transferases (GSTs) yielding glutathione S -conjugates that are more water-soluble and often less reactive than their parent compounds. Such inactivation is protective against lung cancer, but a major mechanism of tumor resistance to platinum compounds. Thus variant alleles associated with reduced GST activity would be expected to be associated with increased cancer risk, but improved response to chemotherapy. Microenvironment: Another example is the matrix metalloprotease family involved in creating and maintaining a microenvironment that facilitates the initial stages of tumor development, but that also has the capacity to degrade the extracellular matrix, including the basement membrane, disruption of which contributes to tumor invasion locally and to distant metastatic spread. In summary , molecular epidemiology can provide a major integrative force both for cancer risk assessment and for prediction of outcome. This project was supported by NCI grants CA55769 and CA70907.