title: MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer.
abstract: We recently analyzed the hypermethylation status of the p16INK4a (p16) gene promoter in normal-appearing mucosa obtained from patients with colorectal cancer. Hypermethylation of p16 was associated with reduced survival of these patients. In the present study, germ line polymorphisms in the folate- and methyl-associated genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR), were analyzed in the same patient cohort to find a possible link between these genetic variants and p16 hypermethylation. Genomic DNA was extracted from blood of patients (n = 181) and controls (n = 300). Genotype analyses were run on an ABI PRISM(®) 7900HT sequence-detection system (Applied Biosystems), using real-time polymerase chain reaction and TaqMan chemistry. The results showed that the genotype distributions of the patient and control groups were similar. No significant differences in cancer-specific or disease-free survival of stage I-III patients according to polymorphic variants were detected, nor were any differences in cancer-specific or disease-free survival detected when patients were subgrouped according to the MTHFR or MTR genotype groups and dichotomized by p16 hypermethylation status in mucosa. However, patients with the MTRR 66 AA/AG genotypes were found to have a significantly worse cancer-specific survival when the mucosa were positive, compared with negative, for p16 hypermethylation (hazard ratio 2.7; 95% confidence interval 1.2-6.4; P = 0.023). In contrast, there was no difference in survival among patients with the MTRR 66 GG genotype stratified by p16 hypermethylation status. These results indicate a relationship between genetic germ-line variants of the MTRR gene and p16 hypermethylation in mucosa, which may affect the clinical outcome of patients with colorectal cancer.
authors.affiliation: Department of General Surgery, University of Gothenburg, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden. yvonne.wettergren@dep-surg.gu.se
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wettergren
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Odin
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D016019:Survival Analysis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase