title: A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation.
abstract: OBJECTIVE
  The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy.
  
  
  METHODS
  Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data.
  
  
  RESULTS
  Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype.
  
  
  CONCLUSIONS
  Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.
authors.affiliation: Research & Innovation (R&I) Company, University of Padua, Padua, Italy. info@researchinnovation.com
authors.forename: Salvatore
authors.initials: S
authors.lastname: Terrazzino
authors.forename: Marco
authors.initials: M
authors.lastname: Agostini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pucciarelli
authors.forename: Lara Maria
authors.initials: LM
authors.lastname: Pasetto
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Friso
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ambrosi
authors.forename: Veronica
authors.initials: V
authors.lastname: Lisi
authors.forename: Alberta
authors.initials: A
authors.lastname: Leon
authors.forename: Mario
authors.initials: M
authors.lastname: Lise
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011379:Prognosis; D011829:Radiation Dosage; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D012074:Remission Induction
chemical_list: D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil