Methylenetetrahydrofolate reductase 677 C-->T polymorphism and risk of proximal colon cancer in north Italy.
OBJECTIVE
Gene silencing by hypermethylation plays an important role in proximal colon carcinogenesis. Conversely, DNA hypomethylation has been associated with distal colon cancer (CLC). Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5',10'-methylenetetrahydrofolate to 5'-methyl tetrahydrofolate, which serves as methyl donor in the remethylation of homocysteine to methionine. A common MTHFR 677 C-->T polymorphism is characterized by reduced catalytic activity, which affects methionine synthesis and DNA methylation. The aim of the study was to investigate the role of MTHFR 677 C-->T gene polymorphism in the tumorigenesis of proximal and distal CLC in a monoinstitutional group of patients in North Italy.


METHODS
One-hundred thirty four consecutive proximal and 142 consecutive distal CLC patients, and 279 control subjects without cancer were genotyped for MTHFR using PCR-restriction fragment-length polymorphism analysis.


RESULTS
The prevalence of the 677 TT genotype was significantly (P = 0.005) lower in patients with proximal tumors (10 of 134, 7%) than in subjects with distal tumors (28 of 142, 20%). Case/control approach indicated that individuals homozygous for the 677 TT allele had a significantly reduced risk (2.8-fold) (adjusted odds ratio, 0.36; 95% confidence intervals, 0.14-0.91) of developing proximal CLC compared with those harboring the wild-type or heterozygous genotype (677 CC or 677 CT). No significant association between CLC risk and TT genotype was observed in patients with distal tumors (odds ratio, 1.01; 95% confidence interval, 0.48-2.14).


CONCLUSIONS
Our findings support a role for MTHFR 677 TT genotype in reducing proximal CLC risk in North Italy.
Toffoli
Giuseppe
G
Experimental and Clinical Pharmacology Unit, Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano (PN), Italy. gtoffoli@cro.it
Gafà
Roberta
R
Russo
Antonio
A
Lanza
Giovanni
G
Dolcetti
Riccardo
R
Sartor
Franca
F
Libra
Massimo
M
Viel
Alessandra
A
Boiocchi
Mauro
M
D000483:Alleles; D003110:Colonic Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D003596:Cytosine; D019175:DNA Methylation; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012016:Reference Values; D012307:Risk Factors; D013941:Thymine
D003596:Cytosine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013941:Thymine