A methylenetetrahydrofolate reductase polymorphism is associated with expression of p16 in human lung cancer.

Kamiya, Hitomi; Kawakami, Kazuyuki; Miyanaga, Tatsuhito; Omura, Kenji; Oda, Makoto; Murakami, Shinya; Watanabe, Yoh

doi:10.3892/or.5.4.911

Cited by 3 publications

(3 citation statements)

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“…Individuals with the homozygous 677T genotype have increased DNA hypomethylation in leukocytes [46] and MTHFR-deficient mice have increased hypomethylation in several tissues. [96] Increased expression of the tumor suppressor gene p16INK4 was found in lung cancer specimens homozygous for the 677T allele, compared with other genotypes; [97] this could be due to effects on DNA methylation.…”

Section: Neoplastic Diseasementioning

confidence: 98%

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene

Schwahn

Rozen

2001

American Journal of PharmacoGenomics

186

151

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5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism by channeling one-carbon units between nucleotide synthesis and methylation reactions. Severe enzyme deficiency leads to hyperhomocysteinemia and homocystinuria, with altered folate distribution and a phenotype that is characterized by damage to the nervous and vascular systems. Two frequent polymorphisms in the human MTHFR gene confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. The C to T change at nucleotide position 677, whose functional consequences are dependent on folate status, has been extensively studied for its clinical consequences. A second polymorphism, an A to C change at nucleotide position 1298, is not as well characterized. Still equivocal are associations between MTHFR polymorphisms and vascular arteriosclerotic or thrombotic disease. Neural tube defects and pregnancy complications appear to be linked to impaired MTHFR function. Colonic cancer and acute leukemia, however, appear to be less frequent in individuals homozygous for the 677T polymorphism.MTHFR polymorphisms influence the homocysteine-lowering effect of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. However, only preliminary evidence exists for gene-drug interactions. This review summarizes the biochemical basis and clinical evidence for interactions between MTHFR polymorphisms and several disease entities, as well as potential interactions with drug therapies. Future investigations of MTHFR in disease should consider the influence of other variants of functionally-related genes as well as the medication regimen of the patients. Animal models for genetic deficiencies in folate metabolism will likely play a greater role in our understanding of folate-dependent disorders.

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Section: Neoplastic Diseasementioning

confidence: 98%

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene

Schwahn

Rozen

2001

American Journal of PharmacoGenomics

186

151

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“…Kraunz et al (32) found that low dietary intake of folate was associated with p16 methylation in tumors of head and neck squamous cell carcinoma patients, and that this relationship was modified by the MTHFR genotype. Kamiya et al (33) examined the association between the MTHFR polymorphism and expression of p16. Their results suggested that folate metabolism can affect carcinogenesis through the expression of p16.…”

Section: Introductionmentioning

confidence: 99%

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

Wettergren

Odin

Carlsson

et al. 2010

Mol Med

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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.

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“…Variants of folate metabolism pathway (Figure 1) genes such as functional polymorphisms of 5,10-methylene-tetrahydrofolate reductase (MTHFR), affect methylation of DNA and tumour suppressor genes (Kamiya et al, 1998;Paz et al, 2002), thereby potentially impacting on tumour behaviour. This coupled with the observation that polymorphisms of this pathway can affect the efficacy of cytotoxic drugs (Maring et al, 2005) has provided a strong rationale for evaluating such variants as prognostic factors.…”

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confidence: 99%

Prognostic significance of folate metabolism polymorphisms for lung cancer

et al. 2007

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Functional nonsynonymous single-nucleotide polymorphisms (nsSNPs) of folate metabolism genes can influence the methylation of tumour suppressor genes, thereby potentially impacting on tumour behaviour. To investigate whether such polymorphisms influence lung cancer survival, we genotyped 14 nsSNPs mapping to methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR); DNA methyltransferase (DNMT2), methylenetetrahydrofolate dehydrogenase (MTHFD1) and methenyltetrahydrofolate synthetase (MTHFS) in 619 Caucasian women with incident disease, 465 with non-small cell (NSCLC) and 154 with small cell lung cancer (SCLC). The most significant association detected was with MTHFS Thr202Ala, with carriers of variant alleles having a worse prognosis (hazard ratio (HR) ¼ 1.49; 95% confidence interval: 1.14 -1.94). Associations were also detected between overall survival (OS) in SCLC and homozygosity for MTHFR 222Val (HR ¼ 1.92; 1.03 -3.58) and between OS from NSCLC and MTRR 175Leu carrier status (HR ¼ 1.36; 1.06 -1.75). While there is evidence that variation in the folate metabolism genes may influence prognosis from lung cancer, current data are insufficiently robust to distinguish individual patient outcome.

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A methylenetetrahydrofolate reductase polymorphism is associated with expression of p16 in human lung cancer.

Cited by 3 publications

References 0 publications

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene

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

Prognostic significance of folate metabolism polymorphisms for lung cancer

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