Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review

Abstract

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

“…24 MTHFR genotype status has been associated with an increased risk of some cancers and a decreased risk of other cancers. 69,70 The overall cancer risk does not appear to be changed. 71 Patients should be counseled that it is important to provide their MTHFR genotype status to any physician who is considering starting them on types of chemotherapy whose activity depends on intracellular concentration of folate (e.g., methotrexate).…”

The MTHFR C677T Polymorphism and Prostate Cancer Risk: New Findings from a Meta-analysis of 7306 Cases and 8062 Controls

“…Such change would disturb the homeostasis of folate metabolism, which was believed to be associated with the occurrence and development of several chronic diseases. Systematic reviews and meta-analysis revealed the MTHFR SNP C677T could increase the risk of developing schizophrenia, congenital heart defects, esophageal cancer, gastric cancer and breast cancer (Lewis et al, 2005;Langevin et al, 2009;Dong et al, 2010;Zhang et al, 2010;Yin et al, 2012) while probably playing as a preventive factor against colorectal cancer and children acute lymphoblastic leukemia (Hubner et al, 2007;Taioli et al, 2009;Yan et al, 2012). There were also many studies concerning the association between prostate cancer risk and SNP C677T, however, no conclusiveness was achieved: Heijmans (Heijmans et al, 2003) suggested MTHFR SNP C677T be a risk factor of prostate cancer in Dutch population, but HSI-CHIN WU found the polymorphism conferred a significant decreased risk of the disease; moreover, some studies showed no statistical relationship between them (Stevens et al, 2008).…”

5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Colon Cancer Risk: a Meta-analysis

“…It is evident that MTHFR is pleomorphic and two most common single nucleotides variants within codon 677 in exon 4 (C to T, ala to val) and codon 1298 in exon 7 (A to C, glu to ala) have been found to be associated with the risk of colon cancer. The codon 677 variant, which lies within the NH2-terminal catalytic domain, encodes a thermolabile enzyme with reduced activity that leads to increased the availability of 5, 10-methylenetetrahydrofolate for DNA synthesis (Frosst et al, 1995;Taioli et al, 2009), which partially explains the reduced risk of colon cancer in subjects carrying the TT genotype in this meta-analysis.…”