Association of polymorphisms MTHFR C677T and A1298C with risk of colorectal cancer, genetic and epigenetic characteristic of tumors, and response to chemotherapy.
OBJECTIVE
The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient outcome after treatment with 5-FU-based chemotherapy to determine the contribution of MTHFR genotypes in the risk of colorectal cancer (CRC) and in the response to therapy.


METHODS
Genomic DNA of 143 Spanish sporadic CRC and 103 controls was analyzed by polymerase chain reaction/restriction fragment length polymorphism and sequencing.


RESULTS
The C677T polymorphism has protective effect on CRC showing TT genotype an odds ratios of 0.06 (95% confidence interval (CI): 0.10-0.32) and the CT of 0.51 (95% CI: 0.3-0.87). MTHFR A1298C polymorphism is not associated with CRC risk. Patients with 1298CC and AC genotypes exhibit worse survival than those with the wild genotype (log rank, p = 0.001), whereas C677T genotypes do not affect patient survival (log rank, p = 0.92). MTHFR 677T allele carriers responded better to 5-FU-based chemotherapy than patients with the wild CC genotype (log rank, p = 0.05). The variant C allele of A1298C affects negatively the response to 5-FU-based chemotherapy (log rank, p = 0.009).


CONCLUSIONS
The variant allele of the C677T has a protective effect on CRC development, whereas the variant allele of the A1298C does not produce any effect on disease risk. Both MTHFR polymorphisms are relevant and independent factors of patient outcome after 5FU-based treatment of CRC, and MTHFR genotyping may be of predictive benefit in selecting treatment regimens.
Fernández-Peralta
Antonia M
AM
Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Daimiel
Lydia
L
Nejda
Nargisse
N
Iglesias
Daniel
D
Medina Arana
Vicente
V
González-Aguilera
Juan J
JJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D018579:Patient Selection; D010641:Phenotype; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil