MTHFR, MTR, and MTRR Polymorphisms in Relation to p16INK4A Hypermethylation in Mucosa of Patients with Colorectal Cancer

作者：Wettergren Yvonne^*; Odin Elisabeth; Carlsson Goran; Gustavsson Bengt

来源：Molecular Medicine, 2010, 16(9-10): 425-432.

DOI：10.2119/molmed.2009.00156

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 (R) 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 2-64: P = 0.023) In contrast, there was no difference in survival among patients with the MTRR 66 GG geno-type stratified by p16 hypermethylation status. These results indicate a relationship between genetic germ-line variants of the

• 出版日期2010-10