Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low activity of arylamine N-acetyltransferase 2 (slow NAT2) was consistently associated with urinary bladder cancer risk. The increased cancer risk attributable to slow NAT2 was more significant when taking gene-environment interactions and gene-gene interactions into account. In urinary bladder, slow NAT2 was no risk factor in subjects who never smoked but became increasingly relevant with increasing lifetime dose of tobacco smoke expressed by an odds ratio of 2.7 for slow NAT2 in extensive smokers. The functional impact of some arylamine N-acetyltransferase 1 variants is controversial. It was published that the NAT1 allele 10 was associated with high enzyme activity and that there was an overrepresentation of carriers of NAT1*10 in bladder and colon cancer, but we could only detect a moderately elevated activity of NAT1*10 and an underrepresentation of fast NAT1 alleles in bladder cancer. Recently, a C/A-polymorphism in intron 1 of cytochrome P450 1A2 was associated with high inducibility and persons with this high inducibility variant were overrepresented in bladder cancer, but only if they were smokers or if they had slow NAT2 genotypes. Numerous studies have shown that glutathione S-transferase M1 deficiency (GSTM1*0/0) increases the risk for lung and bladder cancer but the overall risk attributable to GSTM1*0/0 was only around 1.3 according to meta-analyses. The GSTM1*0/0 genotype appears to be the best established metabolic susceptibility factor. Several independent experimental approaches showed that GSTM1 decreases mutagenicity of reactive epoxides and it was shown that carriers of GSTM1*0/0 were at increased risk for several types of cancer and other diseases. There are also studies which showed no effects of GSTM1, a result which is compatible with the assumption that GSTM1*0/0 is a susceptibility factor of moderate strength. GSTM1*0/0 may, however, become a dominant risk factor in certain gene-gene combinations such as the combination with highly active CYP1A1 gene variants or in combination with specific types of exposure. Specific precautions have to be taken in the design of molecular epidemiological studies on risk factors with moderate strength; some requirements for high quality molecular epidemiological studies will be discussed in this article. Molecular epidemiology is an increasingly powerful approach to understand carcinogenesis and may be used in the future to individualize cancer prevention strategies.
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PMID:Polymorphisms in xenobiotic conjugation and disease predisposition. 1002 51

Studies on the role of genetically polymorphic enzymes like cytochrome P450 1A1, arylamine N-acetyltransferase 2 or glutathione S-transferase M1 as cancer susceptibility factors date back more than 20 years, and some associations have been confirmed in several studies and meta-analyses. Overall, the extent of risk modulation due to these polymorphisms is only moderate but remains epidemiologically relevant. The role of some of these polymorphisms in human health may even be ambiguous: rapid acetylation, for example, protects from urinary bladder cancer but appears to increase the risk of laryngeal, lung and colon cancer. The first genetic polymorphisms in xenobiotics transporters such as P-gp (MDR1) and MRP2 have recently been identified. These polymorphisms may have great impact as cancer susceptibility factors as well as factors modulating the outcome of cancer treatment. Enzymes involved in generation or detoxification of reactive oxygen species also have to be considered; one of these enzymes, myeloperoxidase, constitutes a relatively strong lung cancer risk factor, as confirmed in 4 independent studies. Other genes, including those coding for DNA repair enzymes, signal transduction and cell growth regulation, may ultimately prove more important than the metabolic enzymes as cancer susceptibility factors. Study designs in molecular genetic epidemiology are evolving; large ongoing prospective trials increasingly allow confirmatory nested case control studies to be performed. However, carefully controlled, large case-control studies will remain the mainstay in molecular genetic epidemiology. Molecular genetic epidemiological evaluation of response to chemoprevention as well as response to the adverse events of cancer chemotherapy are likely to provide results that may be useful for individualized prevention and treatment in the near future. Since routine genotyping of all persons is now feasible, something like a genotype passport may soon become reality, and molecular and clinical epidemiological studies will have to provide the basis for understanding how to use genotype data for the benefit of the population.
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PMID:Molecular genetics of cancer susceptibility. 1097 Dec 8