title: Association of RRM1 -37A>C polymorphism with clinical outcome in colorectal cancer patients treated with gemcitabine-based chemotherapy.
abstract: BACKGROUND
  To investigate whether single nucleotide polymorphisms (SNPs) in gemcitabine (GMB) metabolism genes were associated with clinical outcome in pre-treated metastatic colorectal cancer (mCRC) patients.
  
  
  METHODS
  SNPs of hCNT1, hENT1, CDA, dCTD and RRM1 genes were evaluated in 95 mCRC patients and detected using TaqMan genotyping assays. Association of genotypes with overall response rate (ORR), time to progression (TTP) and overall survival (OS) was tested by univariate and multivariate analysis. RRM1 -37A>C polymorphism was correlated with GMB IC50 value and with the RRM1 gene expression level in CRC cell lines.
  
  
  RESULTS
  The ORR was 38.9%. The median TTP and OS were 4 and 14.3 months, respectively. By multivariate analysis, patients carrying the RRM1 -37CC genotype or the CDA A-76 C-containing allele had a significantly higher likelihood of achieving a tumour response. RRM1 -37A>C polymorphism remained associated with clinical efficacy (TTP). In vitro experiments, in CRC cell lines, showed that the RRM1 A-37C genotype was associated with the levels of RRM1 expression and with GMB IC50 values. Finally, the down-regulation of RRM1 with a specific siRNA strongly influenced GMB sensitivity.
  
  
  CONCLUSIONS
  RRM1 -37A>C polymorphism may represent a useful biomarker to select mCRC patients most likely to benefit from GMB-based salvage therapy.
authors.affiliation: Department of Oncology, Clinic University of Navarra, Pamplona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez
authors.forename: V
authors.initials: V
authors.lastname: Boni
authors.forename: A
authors.initials: A
authors.lastname: Hernández
authors.forename: N
authors.initials: N
authors.lastname: Bitarte
authors.forename: R
authors.initials: R
authors.lastname: Zarate
authors.forename: M
authors.initials: M
authors.lastname: Ponz-Sarvisé
authors.forename: A
authors.initials: A
authors.lastname: Chopitea
authors.forename: E
authors.initials: E
authors.lastname: Bandres
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Foncillas
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine