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Role of MTHFR polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

By altering both DNA methylation and nucleotide synthesis, folate metabolism is thought to contribute to colorectal carcinogenesis. We examined the role of folate metabolism in three different phenotypes of sporadic colorectal cancers (CRCs), phenotypes that were classified by the status of microsatellite instability (MSI) and chromosomal instability (CIN): MSI-H, microsatellite stability (MSS)/aneuploidy, and MSS/diploid.

Patients and methods

A total of 195 sporadic colorectal tumors and another 195 age- and gender-matched healthy volunteers in Taipei-Veteran General Hospital and Taipei City Hospital were collected. We analyzed for MTHFR (methylenetetrahydrofolate reductase) polymorphisms (C677T, A1297C), folate, and vitamin B12 levels. We determined MSI status and DNA ploidy with fluorescent polymerase chain reaction and flow cytometry. Relations between clinicopathological variables and molecular variables were analyzed by χ 2 tests (with Yates’ correction) for categorical variables and Student’s t test for numerical variables.

Results

Folate levels (5.02±4.43 ng/ml) were significantly lower in cancer patients than in controls (7.22±4.46 ng/ml). Vitamin B12 level was similar between cancer patients and controls. The frequency of the TT genotype of MTHFR C627T (12.3%) was slightly higher than controls (8.2%), but it did not reach statistical significance (p=0.174). Within the low-folate group (<5 ng/ml), the frequency of the TT genotype in cancer patients (14.4%) was significantly higher than in controls (4.6%). Sixteen patients who had MSI-H CRC (8.2%) had a significantly higher frequency of TT MTHFR (37.5%) and lower folate levels (3.56±2.41 ng/ml) than patients with MSS tumors (10.1%, 5.14±3.72 ng/ml). Patients with MSS/aneuploid tumors had significantly lower folate levels (4.50±3.06 ng/ml) than those with MSS/diploid tumors (6.69±4.73 ng/ml).

Conclusion

Folate deficiency and the MTHFR genetic polymorphism play an important role in colorectal carcinogenesis, including MSI and CI.

Synopsis

Folate metabolism plays an important role in colorectal carcinogenesis. We demonstrate that patients with MSI-H tumors had higher frequency of TT MTHFR C627T (37.5%), and patients with MSS/aneuploid tumor had lower folate level (4.50±3.06 ng/ml).

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Abbreviations

CEA:

carcinoembryonic antigen

CIN:

chromosomal instability

CRC:

colorectal cancer

HNPCC:

hereditary nonpolyposis colorectal cancer

MSI-H:

high microsatellite instability

MSS:

microsatellite stability

MTHFR:

methylenetetrahydrofolate reductase

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Acknowledgement

This study was supported in part by grants from the Taipei Veterans General Hospital (VGH94-0172 and VGH94-0245).

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Authors and Affiliations

  1. Department of Surgery, Division of Colon & Rectal Surgery, Taipei Veterans General Hospital, National Yang-Ming University, No 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan

    Shih-Ching Chang, Jen-Kou Lin, Shung-Haur Yang & Huann-Sheng Wang

  2. Department of Clinical Pathology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan

    Pei-Ching Lin

  3. Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan

    Anna Fen-Yau Li

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  1. Shih-Ching Chang
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Correspondence to Shih-Ching Chang.

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Chang, SC., Lin, PC., Lin, JK. et al. Role of MTHFR polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers. Int J Colorectal Dis 22, 483–489 (2007). https://doi.org/10.1007/s00384-006-0190-x

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