title: Combined effect of genetic polymorphisms in P53, P73, and MDM2 on non-small cell lung cancer survival.
abstract: BACKGROUND
  Multiple biologically relevant polymorphisms may have more accurate prediction of cancer prognosis compared with single polymorphism because of the modest effect. This study investigated whether the functional polymorphisms in P53 pathway genes, P53 Arg72Pro (rs1042522), P73 G4C14-to-A4T14 (rs2273953 and rs1801173), and MDM2 T309G (rs2279744), alone or in combination, affect survival in advanced non-small cell lung cancer (NSCLC) patients.
  
  
  METHODS
  A total of 199 stage III-IV NSCLC patients with platinum-based chemotherapy were recruited between 2002 and 2004. Associations between genotypes and survival were assessed using Kaplan-Meier method. Cox proportional hazard models were performed to identify significant variables.
  
  
  RESULTS
  During the median 26.5 months of follow-up, the P53 Pro/Pro genotype was strongly associated with shorter overall survival compared with the Arg/Arg genotype (12.0 versus 20.0 months; log-rank p = 0.002; hazard ratio = 1.86; 95% confidence interval [CI], 1.15-3.02). Pairwise combination analysis showed that patients carrying the variant P53 Pro/Pro-P73 GC/GC or P53 Pro/Pro-MDM2 GG genotypes had survival time only half of that for those carrying the wild-type genotypes, with hazard ratio being 2.47 (95% CI, 1.20-5.10) and 2.00 (95% CI, 1.15-3.46), respectively. Furthermore, a combined effect was seen with survival time being gradually shorter with increasing number of unfavorable genotypes in these three genes (p(trend) = 0.039), indicating a gene-dose effect in association with survival.
  
  
  CONCLUSIONS
  These findings suggest that genetic polymorphisms in the P53 pathway may be promising biomarkers for individualized chemotherapy and prognosis of NSCLC patients.
authors.affiliation: Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.forename: Shengyu
authors.initials: S
authors.lastname: Duan
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.forename: Songyi
authors.initials: S
authors.lastname: Lin
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.forename: Dianke
authors.initials: D
authors.lastname: Yu
authors.forename: Shaofa
authors.initials: S
authors.lastname: Nie
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D016190:Carboplatin / 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; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D001952:Bridged-Ring Compounds; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; C495901:TP53 protein, human; C000606460:TP73 protein, human; D043823:Taxoids; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000077150:Oxaliplatin; C080625:taxane; D014747:Vinblastine; D016190:Carboplatin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin; D000077235:Vinorelbine