Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and hereditary colorectal cancer with or without microsatellite instability

Plaschke, Jens; Schwanebeck, Uta; Pistorius, Steffen; Saeger, H. D.; Schackert, Hans K.

doi:10.1016/s0304-3835(02)00633-x

Cited by 38 publications

(39 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15) Two other studies suggested a slightly decreased risk of colon or colorectal cancer associated with the 1298CC genotype among physicians in the United States 22) and in Hawaii, 14) whereas the 1298CC genotype was associated with a statistically nonsignificant increase in the risk in Germany. 16) In the present study, individuals with the 1298CC genotype showed a small, statistically nonsignificant increase in the overall risk of colorectal cancer and a significant increase in the risk when alcohol consumption was high. Moreover, a 2-fold increase in the risk associated with the 1298CC genotype was noted for proximal and distal colon cancer.…”

Section: Discussionmentioning

confidence: 39%

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

et al. 2004

View full text Add to dashboard Cite

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies. uch attention has recently been drawn to the role of folate metabolism in colorectal carcinogenesis.1, 2) Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism. It irreversibly converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is the major form of folate in blood.2) The substrate of MTHFR, 5,10-methylenetetrahydrofolate, is required for conversion of deoxyuridylate to thymidylate. Depletion of 5,10-methylenetetrahydrofolate results in uracil misincorporation into DNA, and removal of this abnormal base may lead to single and double strand breaks.3, 4) Furthermore, insufficient thymidylate can increase DNA misrepair, resulting in overall DNA damage in the cell.5) On the other hand, 5-methyltetrahydrofolate provides the methyl group for methylation of homocysteine to methionine. Imbalanced DNA methylation, i.e., global genomic hypomethylation and methylation of usually unmethylated CpG sites, has been implicated in colorectal carcinogenesis. [6][7][8] Two common functional polymorphisms are known in the MTHFR gene; one is the C677T polymorphism in exon 4, resulting in an alanine-to-valine substitution at codon 222, 9) and the other is the A1298C in exon 7, resulting in a substitution of glutamate with alanine at codon 429.10) Individuals who are homozygous for the vari...

show abstract

Section: Discussionmentioning

confidence: 39%

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Results from the few previous studies of MTHFR Glu 429 Ala and colorectal cancer risk have been inconsistent, with a statistically significant reduced risk associated with Ala/Ala versus Glu/Glu having been observed in just one study (32). The point estimates from other studies have suggested reduced (34,39,45,47,54), null (31,42), and increased (35,37,41) risks of colorectal cancer for Ala/Ala versus Glu/ Glu. In a meta-analysis of eight previous studies, Ala/Ala versus Glu/Glu was associated with a nonsignificant 17% reduction in colorectal cancer risk, however, statistically significant heterogeneity between studies was observed (11 (59,60).…”

Section: Resultsmentioning

confidence: 89%

“…The results were similar to that from our analysis of dietary methyl status (P test for interaction >0.13; data not shown). Because this analysis of interaction with dietary methyl status was based on grouping the variant carriers, and the main effect of MTHFR Ala 222 Val has been observed to behave in a recessive manner, we also conducted this analysis with Vitamin B 12 is transported by TCN II and is a cofactor to MTR, the function of which is related to MTRR and BHMT, thus, we examined whether total vitamin B 12 intake (including dietary and supplemental sources) modified the associations for BHMT Arg 239 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) and nested case-control studies (10,(46)(47)(48). In addition, our finding that the inverse association was stronger for colon cancers versus rectal cancers was consistent with some (47,48), although not all previous studies (38,40,46).…”

Section: Resultsmentioning

confidence: 99%

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

Koushik

Kraft

Fuchs

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

The Ala 222 Val single nucleotide polymorphism (SNP) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in one-carbon metabolism, has been associated with colorectal cancer risk. Many enzymes are involved in one-carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-carbon metabolism pathway in relation to the risk of colorectal cancer in a case-control study nested in the

show abstract

“…Methylene tetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metabolism and subsequently plays a key role in DNA synthesis and methylation. 8 The role of this enzyme is to catalyse the irreversible reaction of 5,10-methyl-tetrahydrofolate (MTHF) to 5-MTHF, which is an integral part of the folate metabolism pathway. 5,10-MTHF is required for DNA synthesis and is in particular involved in uracil incorporation, whereas its product 5-MTHF is the methyl donor for regeneration of methionine from homocysteine for methylation reactions.…”

Section: Introductionmentioning

confidence: 99%

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

et al. 2009

View full text Add to dashboard Cite

Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and hereditary colorectal cancer with or without microsatellite instability

Cited by 38 publications

References 19 publications

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

Contact Info

Product

Resources

About