Polymorphisms in Metabolic Genes
aMilan Italy and School of Public Health, Genetics Research Institute, UMDNJ, NJ, United States, bOspedale Maggiore IRCCS, Milan Italy
Aim: Metabolic gene polymorphisms are involved in detoxification and activation of several endogenous and exogenous carcinogens. The role of these low penetrance genetic variants in human cancer etiology has been studied for many years with conflicting results, often due to the low power and small sample size of the studies. Methods: A large pooled analysis project (Genetic Susceptibility to Environmental Carcinogenesis, GSEC) involving 152 studies from 82 investigators, and currently containing over 24,000 cases of cancer of the lung, bladder, head and neck, breast, colon, skin, leukemia, prostate, ovary, and uterus, and over 28,000 controls, has been used to examine issues of gene gene and gene environment interaction in human carcinogenesis. Because data on genotypes, exposures, demographics, and others are available for each individual, the GSEC data base is ideal for testing hypotheses that cannot be done in a metaanalysis, with high power. Results: Among the studies that have been done using the data base are: Metabolic gene polymorphism frequencies in control populations; Current smoking, occupation, NAT2 and bladder cancer; interaction between asbestos exposure and GSTM1 and T1 genotype in lung carcinogenesis; Microsomal epoxide hydrolase polymorphisms and lung cancer risk; Interaction between GST genotypes, smoking and lung cancer risk; Pooled and meta-analysis of gstm1 and bladder cancer; Metabolic gene polymorphisms and lung cancer below the age of 45 years; CYP1A1 t3801c polymorphism and lung cancer; CYP1A1 and gstm1 genetic polymorphisms and lung cancer risk in Caucasian nonsmokers; heterogeneity in the association between CYP1A1, GSTM1 and CYP2E1 and lung cancer; association between genetic polymorphisms and tobacco exposure among controls; interaction between gstm1 and smoking on colo-rectal cancer; meta and pooled analysis of GSTM1, GSTT1, GSTP1, CYP1A1 polymorphisms and risk of head and neck cancers. Conclusions: The results from most of these studies indicate that the associations between any single genetic variant in metabolic susceptibility genes and cancer is weak or nonexistent. However, several interesting cases of gene gene and gene environment interaction were detected, which could not have been seen with single small studies. A model illustrating the role of multiple genetic and environmental frisk factors, which can be used to uncover stronger associations than those seen for individual genes one at a time has been developed.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 701 (Molecular oncogenesis).