title: Prognostic significance of thymidylate synthase polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy.
abstract: OBJECTIVE
  There is a lack of prognostic factors of preoperative chemoradiation for locally advanced rectal cancer. Thymidylate synthase (TS) is the most important target of 5-fluorouracil; three main genetic polymorphisms of TS have been described. We analysed the prognostic value of these in patients with locally advanced rectal cancer treated with fluoropyrimidine-based chemoradiation.
  
  
  METHODS
  Ninety-nine patients treated between November 2001 and March 2009 were included. All were treated by radiotherapy (5040 cGy) and concomitant fluoropyrimidine-based chemotherapy. Three polymorphisms were analysed: (i) a double (2R) or triple (3R) repeat of a 28 base pair (bp) tandem sequence upstream of the ATG codon initiation site in the 5'-terminal regulatory region, (ii) a functional G > C single nucleotide polymorphism present in the second repeat of the 3R alleles and (iii) a 6 bp deletion at nucleotide 1494 in the 3'-untranslated region. DNA was extracted from paraffin-embedded core biopsies taken from the tumour and the genotype was analysed using polymerase chain reaction restriction fragment length polymorphism.
  
  
  RESULTS
  The 6 bp polymorphism was significantly associated with disease-free survival (+ 6 bp/+ 6 bp vs-6 bp/-6 bp, P = 0.032 logistic regression). No differences were found in disease-free survival according to the other polymorphisms studied. No relationship was observed between the different TS genotypes and pathological regression.
  
  
  CONCLUSIONS
  The study suggests that the TS 6 bp polymorphism may be a predictor of disease-free survival in patients with locally advanced rectal cancer treated with fluoropyrimidine-based chemoradiation.
authors.affiliation: Department of Medical Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain. varrazubi@gmail.com
authors.forename: V
authors.initials: V
authors.lastname: Arrazubi
authors.forename: J
authors.initials: J
authors.lastname: Suárez
authors.forename: D
authors.initials: D
authors.lastname: Guerrero
authors.forename: M
authors.initials: M
authors.lastname: Gómez
authors.forename: A
authors.initials: A
authors.lastname: Viúdez
authors.forename: F
authors.initials: F
authors.lastname: Arias
authors.forename: E
authors.initials: E
authors.lastname: Balén
authors.forename: R
authors.initials: R
authors.lastname: Vera
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001483:Base Sequence; D000069287:Capecitabine; D059186:Chemoradiotherapy, Adjuvant; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D017384:Sequence Deletion; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D000069287:Capecitabine; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil