Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the chemosensitivity of colorectal cancers to fluorouracil (5-FU) by increasing intracellular 5, 10-methylenetetrahydrofolate. The effect of this polymorphism on the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP) in colorectal cancer was investigated. The MTHFR C677T polymorphism was analysed and TS, DPD, OPRT and TP mRNA expression was measured in tumour and adjacent normal mucosal tissue. In all patients, the genotypes of the tumour and normal tissues were identical. No differences were found in the expression of TS, DPD or TP mRNA by genotype in either tumour or normal tissue. Although the OPRT mRNA level in tumour tissue was not associated with the genotype, normal mucosa with the TT genotype showed a significantly higher OPRT mRNA level than mucosa with other genotypes. The MTHFR C667T polymorphism is not associated with intratumoural expression of TS, DPD, OPRT or TP.
FrosstPBlomHJMilosRGoyettePSheppardCAMatthewsRG: A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet1995; 10: 111–113.
2.
BagleyPJSelhubJ: A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA1998; 95: 13217–13220.
3.
KuhnJG: Fluorouracil and the new oral fluorinated pyrimidines. Ann Pharmacother2001; 35: 217–227.
4.
SohnKJCroxfordRYatesZLucockMKimYI: Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst2004; 96: 134–144.
5.
EtienneMCIlcKFormentoJLLaurent-PuigPFormentoPCheradameS: Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: Relationships with 5-fluorouracil sensitivity. Br J Cancer2004; 90: 526–534.
6.
EtienneMCFormentoJLChazalMFrancoualMMagneNFormentoP: Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients. Pharmacogenetics2004; 14: 785–792.
7.
CohenVPanet-RaymondVSabbaghianNMorinIBatistGRozenR: Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: A novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res2003; 9: 1611–1615.
8.
JakobsenANielsenJNGyldenkerneNLindebergJ: Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol2005; 23: 1365–1369.
9.
StevensonJPRedlingerMKluijtmansLASunWAlgazyKGiantonioB: Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer. J Clin Oncol2001; 19: 4081–4087.
10.
WisotzkeyJDTomanJBellTMonkJSJonesD: MTHFR (C677T) polymorphisms and stage III colon cancer: Response to therapy. Mol Diagn1999; 4: 95–99.
11.
SalongaDDanenbergKDJohnsonMMetzgerRGroshenSTsao-WeiDD: Colorectal tumours responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res2000; 6: 1322–1327.
12.
IchikawaWUetakeHShirotaYYamadaHTakahashiTNiheiZ: Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Br J Cancer2003; 89: 1486–1492.
13.
LordRVSalongaDDanenbergKDPetersJHDeMeesterTRParkJM: Telomerase reverse transcriptase expression is increased early in the Barrett's metaplasia, dysplasia, adenocarcinoma sequence. J Gastrointest Surg2000; 4: 135–142.
14.
HeidCAStevensJLivakKJWilliamPM: Real time quantitative PCR. Genome Res1996; 6: 986–994.
15.
GibsonUEHeidCAWilliamsPM: A novel method for real time quantitative RT-PCR. Genome Res1996; 6: 995–1011.
16.
MoritaHTaguchiJKuriharaHKitaokaMKanedaHKuriharaY: Genetic polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation1997; 95: 2032–2036.
17.
StankovaJShangJRozenR: Antisense inhibition of methylenetetrahydrofolate reductase reduces cancer cell survival in vitro and tumor growth in vivo. Clin Cancer Res2005; 11: 2047–2052.
18.
BackusHHPinedoHMWoutersDPadronJMMoldersNvan Der WiltCL: Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates. Int J Cancer2000; 87: 771–778.
19.
MaJStampferMJGiovannucciEArtigasCHunterDJFuchsC: Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res1997; 57: 1098–1102.
20.
KawakamiKRuszkiewiczABennettGMooreJWatanabeGIacopettaB: The folate pool in colorectal cancers is associated with DNA hypermethylation and with a polymorphism in methylenetetrahydrofolate reductase. Clin Cancer Res2003; 9: 5860–5865.
21.
KawakamiKOmuraKKanehiraEWatanabeG: Methylenetetrahydrofolate reductase polymorphism is associated with folate pool in gastrointestinal cancer tissue. Anticancer Res2001; 21: 285–289.
22.
HerbigKChiangEPLeeLRHillsJShaneBStoverPJ: Cytoplasmic serine hydroxy-methyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J Biol Chem2002; 277: 38381–38389.
23.
OppenheimEWAdelmanCLiuXStoverPJ: Heavy chain ferritin enhances serine hydroxy-methyltransferase expression and de novo thymidine biosynthesis. J Biol Chem2001; 276: 19855–19861.
24.
PullarkatSTStoehlmacherJGhaderiVXiongYPInglesSASherrodA: Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J2001; 1: 65–70.
