title: Differential effect of polymorphisms of CMPK1 and RRM1 on survival in advanced non-small cell lung cancer patients treated with gemcitabine or taxane/cisplatinum.
abstract: BACKGROUND
  To determine whether genetic variations in CMPK1 or RRM1, which impact the pharmacodynamics of gemcitabine, differentially affect the outcomes of non-small cell lung cancer (NSCLC) patients treated with gemcitabine or taxane/cisplatinum.
  
  
  METHODS
  We conducted retrospective study evaluating the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane (159)/cisplatinum and 14 tagging single-nucleotide polymorphisms (tSNPs): 4 in CMPK1 and 10 in RRM1.
  
  
  RESULTS
  The wild-type genotypes of CMPK1 IVS1+1057 and IVS1-928 were associated with shorter overall survival in patients treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 1.97 and 1.89; Cox pBonferroni = 0.008 and 0.020), whereas this effect was not observed in patients treated with taxane/cisplatinum. No associations were observed for the other 2 CMPK1 or 10 RRM1 tSNPs. Analysis of the interaction between the CMPK1 and RRM1 genes showed that the survival of patients with CMPK1 IVS1+1057 CC and RRM1 IVS1-2374 TT, IVS7+25 AA, IVS7-425 AA, or IVS8+287 TT was significantly shorter when they were treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 3.00, 2.89, 3.14, and 3.00; Cox pBonferroni = 0.007, 0.012, 0.006, and 0.007). However, these effects were not observed in patients treated with taxane/cisplatinum.
  
  
  CONCLUSIONS
  These findings suggest that polymorphisms of CMPK1 and their combination with those of RRM1 are helpful in identifying patients who will benefit less from a gemcitabine/cisplatinum as the first-line regimen.
authors.affiliation: Center for Lung Cancer, Inha University Hospital, Incheon, South Korea. jsryu@inha.ac.kr
authors.forename: Jeong-Seon
authors.initials: JS
authors.lastname: Ryu
authors.forename: Eun-Soon
authors.initials: ES
authors.lastname: Shin
authors.forename: Hae-Seong
authors.initials: HS
authors.lastname: Nam
authors.forename: Hyeon-Gyu
authors.initials: HG
authors.lastname: Yi
authors.forename: Jae-Hwa
authors.initials: JH
authors.lastname: Cho
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Kim
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D001952:Bridged-Ring Compounds; D004273:DNA, Neoplasm; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C080625:taxane; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase; D002945:Cisplatin; D000093542:Gemcitabine