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GSTM-1 and NAT2 and genetic alterations in colon tumors
M L Slattery1, Karen Curtin, K Ma
1Health Research Center, Department of Family and Preventive Medicine, 375 Chipeta Way, Suite A, University of Utah, Salt Lake City, UT 84108, USA.
Objective:
Phase II metabolizing enzymes such as glutathione S-transferases and N-acetyltransferase are involved in the detoxification of carcinogens. Genetic variants of genes coding for these enzymes have been evaluated as to their association with colon cancer, both as independent risk factors and as effect modifiers for associations with diet and cigarette smoking. In this study, we evaluate associations between the GSTM-1 genotype and the NAT2-imputed phenotype and acquired mutations in tumors.
Methods:
Data is taken from a set of 1836 cases and 1958 controls with colon cancer who were part of a large case-control study of colon cancer and whose tumors were previously analyzed for Ki-ras, p53, and microsatellite instability (MSI). We also evaluate the modifying effects of these genetic variants with diet and cigarette smoking, factors previously identified as being associated with specific tumor alterations.
Results:
Neither GSTM-1 nor the NAT2-imputed phenotype was independently associated with Ki-ras, p53, or MSI. Cigarette smoking significantly increased the risk of tumors involving the MSI pathway. Additionally, cigarette smoking doubled the risk of p53 transversion mutations among those who were GSTM-1 present. Cases were slightly more likely to have a p53 mutation if they frequently consumed red meat and had the imputed NAT2 intermediate/rapid phenotype relative to slow phenotype/infrequent consumers of red meat (OR 2.0, 95% CI 1.3-3.0 for intermediate/rapid).
Conclusions:
These data provide support that diet and cigarette smoking may be associated with specific disease pathways, although GSTM-1 and NAT2 do not independently appear to alter susceptibility to these diet and lifestyle factors.
Insights
Genetic variants in glutathione S-transferases (GSTM-1) and N-acetyltransferase (NAT2) do not independently affect colon cancer risk. However, cigarette smoking and diet are linked to specific tumor mutations and pathways.
Area of Science:
- Oncology
- Genetics
- Molecular Epidemiology
Background:
- Phase II metabolizing enzymes, including glutathione S-transferases (GSTM-1) and N-acetyltransferase (NAT2), are crucial for detoxifying carcinogens.
- Genetic variations in these enzymes are investigated for their role in colon cancer development and their interaction with environmental factors like diet and smoking.
Purpose of the Study:
- To investigate the association between GSTM-1 genotype, NAT2-imputed phenotype, and acquired mutations (Ki-ras, p53, MSI) in colon tumors.
- To evaluate the modifying effects of these genetic variants on the relationship between diet, cigarette smoking, and specific tumor alterations.
Main Methods:
- Analysis of data from 1836 colon cancer cases and 1958 controls.
- Tumor analysis for Ki-ras, p53 mutations, and microsatellite instability (MSI).
- Assessment of GSTM-1 genotype and NAT2-imputed phenotype in relation to tumor characteristics and lifestyle factors.
Main Results:
- No independent association was found between GSTM-1 or NAT2 and Ki-ras, p53 mutations, or MSI.
- Cigarette smoking was associated with an increased risk of MSI-pathway tumors and p53 transversion mutations in individuals with the GSTM-1 present genotype.
- Frequent red meat consumption combined with an intermediate/rapid NAT2 phenotype showed a higher likelihood of p53 mutations.
Conclusions:
- Diet and cigarette smoking appear to be associated with specific colon cancer pathways.
- GSTM-1 and NAT2 genetic variants do not seem to independently modify susceptibility to these diet and lifestyle-related factors in colon cancer.