Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: Cross‐sectional and prospective studies and meta‐analyses of 75,000 cases and 93,000 controls

Abstract

Global DNA hypomethylation associates with development of cancer. DNA hypomethylation also associates with hyperhomocysteinemia and MTHFR c.677C>T homozygosity, both of which may associate with increased risk of cancer. We tested the putative association of hyperhomocysteinemia with cancer and the association of the MTHFR c.677TC>T variant with hyperhomocysteinemia and with cancer. We performed a cross-sectional study of 5,949 Danish general population adults, a prospective study of 9,235 Danish general population adults with up to 60 years of registry surveillance, and meta-analyses of 231 studies including 74,671 cases and 93,344 controls. Cross-sectionally, plasma homocysteine levels were 12.9 and 11.6 μmol/L in those with and without cancer (p < 0.0001). However, homocysteine levels increased with age and age-adjusted odds ratio for any cancer in those with homocysteine levels >12.4 versus < 9.4 μmol/L did not differ from 1.0. In cancer-free participants, plasma homocysteine levels were 14.7 and 11.7 μmol/L in MTHFR c.677C>T homozygtes and noncarriers (p < 0.0001). Prospectively, hazard ratios for any cancer and for cancer subtypes in MTHFR c.677C>T homozygotes versus noncarriers did not differ from 1.0. However, in meta-analyses odds ratio for MTHFR c.677C>T homozygotes versus noncarriers were 1.07 (95% CI: 1.01-1.12) for any cancer, 1.77 (1.17-2.68) for esophagus cancer, 1.40 (1.19-1.66) for gastric cancer and 0.85 (0.77-0.94) for colorectal cancer. Increased plasma homocysteine levels are not associated with an increased age-adjusted risk of any cancer. However, MTHFR c.677C>T homozygosity with lifelong hyperhomocysteinemia and hence hypomethylation associate with increased risk of esophagus and gastric cancer, and with decreased risk of colorectal cancer.

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

“…• MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss • MTHFR polymorphism genotyping should not be ordered for at-risk family members • A clinical geneticist who serves as a consultant for a patient in whom an MTHFR polymorphism(s) is found should ensure that the patient has received a thorough and appropriate evaluation for his or her symptoms • If the patient is homozygous for the "thermolabile" variant c.665C→T, the geneticist may order a fasting total plasma homocysteine, if not previously ordered, to provide more accurate counseling • MTHFR status does not change the recommendation that women of childbearing age should take the standard dose of folic acid supplementation to reduce the risk of neural tube defects as per the general population guidelines [71][72][73][74][75][76][77] Lack of evidence for MTHFR polymorphism testing | HICKEY et al ACMG PrACtiCe Guidelines recent study suggests that the effect is ameliorated in populations with folate supplementation. 61 There is no known contraindication to taking oral contraceptives.…”

“…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). In individuals who have a known thrombophilia, such as factor V Leiden or prothrombin c.*97G→A, most available studies support the contention that MTHFR genotype status does not alter their thrombotic risk to a clinically significant degree.…”

Impact of methylenetetrahydrofolate reductase polymorphisms and folate intake on the risk of gastric cancer and their association with Helicobacter pylori infection and tumor site

“…Studies conducted in China (Qin et al, 2008), Iran (Saberi et al, 2012), Korea (Cui et al, 2010), Mexico (ZunigaNoriega et al, 2007;Galvan-Portillo et al, 2009), Norway (Vollset et al, 2007), and Denmark (Zacho et al, 2011) identified a significant association of the MTHFR C677T polymorphism with gastric cancer. Studies in China, Iran, and Denmark indicated a significantly increased risk of gastric cancer, with ORs ranging from 1.4-2.6 (Qin et al, 2008;Zacho et al, 2011;Saberi et al, 2012). In contrast, several other studies have indicated that MTHFR 677TT significantly protects against gastric cancer (Galvan-Portillo et al, 2009;Cui et al, 2010).…”

Methylenetetrahydrofolate Reductase C677T Polymorphism and Cervical Cancer Risk: a Meta-Analysis

“…Because the DNA methylation plays a critical role in regulation of gene expression and maintenance of genomic stability, the aberrations in normal methylation patterns have been associated with the development of cancer by impairing the DNA methylation (Cheng et al, 1997). More importantly, the homozygous variant genotype MTHFR 677TT has been associated with risk for many different types of cancer, including colorectal cancer, gastric cancer and breast cancer (Taioli et al, 2009;Dong et al, 2010;Zacho et al, 2011).…”