TY - JOUR
T1 - 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
AU - Zacho, Jeppe
AU - Yazdanyar, Shiva
AU - Bojesen, Stig E
AU - Tybjærg-Hansen, Anne
AU - Nordestgaard, Børge G
PY - 2011/2/1
Y1 - 2011/2/1
N2 - 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.
AB - 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.
U2 - 10.1002/ijc.25375
DO - 10.1002/ijc.25375
M3 - Journal article
SN - 0020-7136
VL - 128
SP - 644
EP - 652
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -
