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.