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

Abstract

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...

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

“…However, the results are greatly inconsistent among various as well as within the same cancer sites. Some of these studies reported that MTHFR 677T allele carriers have reduced risks of colorectal [5][6][7][8][9], leukemia [10][11][12], and lung cancers [29]. In contrast, other studies reported elevated risks of esophageal [17], gastric [18], ovarian [30], cervical [14], bladder [13], colorectal [31,32], and lung cancers [33] for MTHFR 677T allele carriers.…”

“…Genotypes with the MTHFR 677T allele have been related to protective effects on colon/rectum cancer [5][6][7][8][9], acute lymphocytic leukemia [10][11][12], and increased cancer risk of the bladder [13], cervix [14], breast [15,16], esophagus [17], and stomach [18]. However, only one epidemiological study estimated the relationship between MTHFR polymorphisms and liver cancer among patients with alcoholic cirrhosis and suggested that the MTHFR 677CC genotype increased the risk of developing HCC among patients with high alcohol consumption [19].…”

MTHFR C677T Polymorphism and Colorectal Cancer Risk in Asians, a Meta-analysis of 21 Studies

“…After discarding overlapping references and those which clearly did not meet the criteria, 22 studies were further assessed for eligibility (Park et al, 1999;Matsuo et al, 2002;Huang et al, 2003;Jiang et al, 2004;Kim et al, 2004;Yin et al, 2004;Jiang et al, 2005;Matsuo et al, 2005;Miao et al, 2005;Otani et al, 2005;Chang et al, 2007;Jin et al, 2007;Cao et al, 2008;Zhang et al, 2008;Cui et al, 2010;Promthet et al, 2010;Yang et al, 2010;Zhu et al, 2010;Kang et al, 2011;Kim et al, 2011;Zhu et al, 2011;Kim et al, 2012). After reviewing each original paper and extracting data, one study was excluded for overlapping data (Jiang et al, 2004).…”

“…As T allele dose increases, this functional polymorphism causes a graded elevation in tHcy in the mild-moderate range, most pronounced in individuals with low dietary folate consumption (Frosst et al, 1995). Thus, considering the potential influence on Zhen Yang*, Xie-Fu Zhang, Hong-Xiang Liu, Yong-Shun, Hao, Chun-Lin Zhao folate metabolism, many epidemiological studies have explored the association between the MTHFR C677T polymorphism and CRC risk, but the results are conflicting (Park et al, 1999;Matsuo et al, 2002;Kim et al, 2004;Yin et al, 2004;Otani et al, 2005;Chang et al, 2007;Cao et al, 2008;Cui et al, 2010;Promthet et al, 2010;Kim et al, 2011;Zhu et al, 2011). Small genetic association studies have various designs, different methodology and insufficient power, and could inevitably increase the risk that chance could be responsible for their conclusions, while combining data from all eligible studies by meta-analysis has the advantage of reducing random error and obtaining precise estimates for some potential genetic associations .…”

MTHFR C677T Polymorphism and Risk of HCC in Patients With Liver Cirrhosis: Role of Male Gender and Alcohol Consumption

“…In fact, carriage of the 677T allele was associated with an elevated risk of developing esophageal (Song et al, 2001), gastric (Shen et al, 2001), ovarian (Gershoni-Baruch et al, 2000), and lung (Siemianowicz et al, 2003) cancer, and with a reduced risk in colorectal (Ma et al, 1997;Slattery et al, 1999;Yin et al, 2004) and lung (Jeng et al, 2003) cancer and in leukemia (Franco et al, 2001;Skibola et al, 1999).…”