Molecular Medicine

, Volume 16, Issue 9–10, pp 425–432 | Cite as

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

  • Yvonne Wettergren
  • Elisabeth Odin
  • Göran Carlsson
  • Bengt Gustavsson
Research Article


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.



We acknowledge the technical skills of M Martinsson, M Åkerström and J Flach. We thank H Björkqvist and A-L Helminen for collecting surgical tissue samples and L Munro, B Sjöberg and M-L Jakobsson for their work with the clinical database. We also thank the staff at the Genomics Core Facility in Gothenburg who performed the genotype analyses.

This work was supported by grants from the Swedish Cancer Society, the University of Gothenburg Foundation, the Assar Gabrielsson Foundation for Cancer Research, the Gustaf V Jubilee Clinic Foundation for Cancer Research and the Ingabritt and Arne Lundberg Foundation.


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Copyright information

© The Feinstein Institute for Medical Research 2010

Authors and Affiliations

  • Yvonne Wettergren
    • 1
  • Elisabeth Odin
    • 1
  • Göran Carlsson
    • 1
  • Bengt Gustavsson
    • 1
  1. 1.Surgical-Oncology Laboratory Department of General SurgeryUniversity of Gothenburg, Plan 1, CK, Sahlgrenska University Hospital/ÖstraGothenburgSweden

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