GSTM-1 and NAT2 and genetic alterations in colon tumors.
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.
Slattery
M L
ML
Health Research Center, Department of Family and Preventive Medicine, 375 Chipeta Way, Suite A, University of Utah, Salt Lake City, UT 84108, USA.
Curtin
Karen
K
Ma
K
K
Schaffer
Donna
D
Potter
John
J
Samowitz
Wade
W
D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D005247:Feeding Behavior; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008019:Life Style; D016015:Logistic Models; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D011795:Surveys and Questionnaires
D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; C478900:NAT2 protein, human