ABSTRACT
BACKGROUND AND AIMS: Evidence is accumulating for a role of folate in the aetiology of colorectal cancer (CRC). The methylenetetrahydrofolate reductase (MTHFR) gene, involved in folate metabolism, is polymorphic in humans. Since it is unknown whether the MTHFR C677T and A1298C polymorphisms alter the risk for CRC, this was the aim of our study. MATERIALS AND METHODS: Genomic DNA from 102 sporadic colorectal adenocarcinoma (SCA) patients and 300 controls was analyzed by polymerase chain reaction followed by restriction digestion for the polymorphisms analyses. RESULTS/FINDINGS: The frequencies of MTHFR C677T and A1298C genotypes were similar in patients and controls. Similar overall risks for disease were seen in individuals with the distinct MTHFR genotypes. However, an excess of the MTHFR 677TT and 677CT genotypes was seen in patients under 50 years, compared with patients at an older age (19.2 vs 13.1% and 61.6 vs 39.5%, respectively; P = 0.04). The differences were more prominent when the frequency of the 677TT plus 677CT genotype was seen in both group of patients (80.8 vs 52.6%, respectively; P = 0.01), and in younger patients compared to controls (80.8 vs 52.3%, P < 0.01). Individuals with the combined genotype had 3.82-fold (95% confidence interval, 1.41-10.42) increased risk of developing SCA under 50 years, compared with those harboring the wild-type genotype. INTERPRETATION/CONCLUSION: These results suggest a role for the MTHFR 677TT plus 677CT genotype in increasing SCA diagnosed at a low age in southeastern Brazil, but additional studies with larger sample sizes should be carried out to clarify this issue.
Subject(s)
Adenocarcinoma , Colorectal Neoplasms , DNA, Neoplasm/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Genetic , Adenocarcinoma/epidemiology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Age Factors , Age of Onset , Biomarkers, Tumor/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Genotype , Humans , Male , Middle Aged , Neoplasm Staging , Polymerase Chain Reaction , Prognosis , Retrospective Studies , Risk FactorsABSTRACT
INTRODUCTION: Glutathione S-transferase enzymes mediate exposure to cytotoxic and genotoxic agents and may be involved in cancer susceptibility. Both glutathione S-transferase mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null variant allele in which the entire gene is absent. The association of glutathione S-transferase null genotype and risk of developing colorectal cancer is not yet fully clarified. METHODS: We tested whether the null genotypes for GSTM1 and GSTT1 genes altered the risk for sporadic colorectal adenocarcinoma in Brazilian patients. Genomic DNA from 102 sporadic colorectal adenocarcinoma patients and 300 controls was analyzed by polymerase chain reaction. RESULTS: Frequencies of GSTM1, GSTT1, and null combined genotypes were similar in patients and controls (49.9 vs. 44.6 percent, 16.6 vs. 17.3 percent, and 8.8 vs. 8 percent, respectively). We found a 1.03-fold (95 percent confidence interval, 0.96-1.10) and 1.08-fold (95 percent confidence interval, 0.99-1.18) increased risk associated with GSTM1 and GSTT1 null genotypes, respectively (P = 0.45 and P = 0.08) and a 1.18-fold (95 percent confidence interval, 0.47-2.90) increased risk associated with the combined null genotype (P = 0.74). The GSTT1 null genotype was more common in patients who were diagnosed before the age of 60 years than in those who were diagnosed at an older age (28.8 vs. 4 percent, respectively; P = 0.0008). CONCLUSIONS: The results suggest that inherited absence of this carcinogen detoxification pathway may not be associated with sporadic colorectal adenocarcinoma in the present cases. However, a higher frequency of GSTT1 null genotype in patients diagnosed before the age of 60 years suggests that this genotype could influence the age of disease onset in Brazil.
