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.
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.
Zacho
Jeppe
J
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Yazdanyar
Shiva
S
Bojesen
Stig E
SE
Tybjærg-Hansen
Anne
A
Nordestgaard
Børge G
BG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003430:Cross-Sectional Studies; D004247:DNA / Q000097:blood; D003718:Denmark / Q000453:epidemiology; D004938:Esophageal Neoplasms / Q000453:epidemiology*; D005260:Female; D006720:Homozygote; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000453:epidemiology*; D008297:Male; D015201:Meta-Analysis as Topic; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology*; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D013274:Stomach Neoplasms / Q000453:epidemiology*
D004247:DNA; D042965:Methylenetetrahydrofolate Reductase (NADPH2)