title: Expression and clinical significance of methylenetetrahydrofolate reductase in patients with colorectal cancer.
abstract: BACKGROUND
  The aim of the study was to investigate the influence of methylenetetrahydrofolate reductase (MTHFR) gene expression levels and MTHFR polymorphism C677T on the outcome of patients with colorectal cancer (CRC). Furthermore, we wanted to evaluate the interaction between MTHFR and thymidylate synthase (TS) and folylpolyglutamate synthase (FPGS) and to investigate the impact of folate concentration on patients with CRC with different MTHFR genotypes.
  
  
  METHODS
  The frequency of MTHFR polymorphism C677T was determined (n = 147), and gene expression levels of MTHFR, TS, and FPGS were quantified with real-time polymerase chain reaction (n = 157). Reduced folates in tissue were measured with a binding assay (n = 40).
  
  
  RESULTS
  We observed a significantly lower concentration of tetrahydrofolate (THF) in patients with CT or TT genotypes compared with patients having the CC genotype. Twenty-six patients with Dukes A to C tumors who had not been subjected to chemotherapy relapsed. Out of these, 18 had CT or TT genotypes, and only 8 had the CC genotype (P = 0.045). Furthermore, 75 patients did not relapse, and out of these, 35 had CT or TT genotypes, and 40 had the CC genotype. The relative gene expression level of MTHFR in patients subgrouped by CC and CT or TT genotypes was significantly lower in carcinomas compared with adjacent mucosa (P < 0.0001 and P < 0.0001, respectively). A significant difference in MTHFR expression level was also observed according to MTHFR genotype in the tumor but not in adjacent mucosa. The MTHFR gene expression level in mucosa was a prognostic parameter independent of the clinicopathologic factors with regard to survival for patients with MTHFR C677T mutation.
  
  
  CONCLUSIONS
  Our results showed that it is possible to identify patients with CRC with a higher risk for relapse. Furthermore, patients with a mutant genotype in combination with low MTHFR expression have a poor clinical outcome.
authors.affiliation: Department of General Surgery, Sahlgrenska University Hospital/ostra, Goteborg, Sweden. elisabeth.odin@dep-surg.gu.se
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Odin
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wettergren
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.forename: Peter V
authors.initials: PV
authors.lastname: Danenberg
authors.forename: Angelo
authors.initials: A
authors.lastname: Termini
authors.forename: Roger
authors.initials: R
authors.lastname: Willén
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D015996:Survival Rate
chemical_list: D012333:RNA, Messenger; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)