title: Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC.
abstract: BACKGROUND
  Platinum agents can cause the formation of DNA adducts and induce apoptosis to eliminate tumor cells. The aim of the present study was to investigate the influence of genetic variants of MDM2 on chemotherapy-related toxicities and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  We recruited 663 patients with advanced NSCLC who had been treated with first-line platinum-based chemotherapy. Five tagging single nucleotide polymorphisms (SNPs) in MDM2 were genotyped in these patients. The associations of these SNPs with clinical toxicities and outcomes were evaluated using logistic regression and Cox regression analyses.
  
  
  RESULTS
  Two SNPs (rs1470383 and rs1690924) showed significant associations with chemotherapy-related toxicities (ie, overall, hematologic, and gastrointestinal toxicity). Compared with the wild genotype AA carriers, patients with the GG genotype of rs1470383 had an increased risk of overall toxicity (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.34-8.02; P = .009) and hematologic toxicity (OR, 4.10; 95% CI, 1.73-9.71; P = .001). Likewise, patients with the AG genotype of rs1690924 showed more sensitivity to gastrointestinal toxicity than did those with the wild-type homozygote GG (OR, 2.32; 95% CI, 1.30-4.14; P = .004). Stratified survival analysis revealed significant associations between rs1470383 genotypes and overall survival in patients without overall or hematologic toxicity (P = .007 and P = .0009, respectively).
  
  
  CONCLUSIONS
  The results of our study suggest that SNPs in MDM2 might be used to predict the toxicities of platinum-based chemotherapy and overall survival in patients with advanced NSCLC. Additional validations of the association are warranted.
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China; State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China. Electronic address: jiqian@fudan.edu.cn.
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gu
authors.affiliation: East China Normal University School of Life Science, Shanghai, China.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China; Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry, University of California, San Diego, La Jolla, CA.
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China.
authors.forename: Haijian
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China.
authors.forename: Jiucun
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Respiratory Disease, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China; Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Fudan University School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Shanghai, China. Electronic address: darulu@hotmail.com.
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017671:Platinum Compounds / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D017671:Platinum Compounds; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Non–small-cell lung cancer; Platinum-based chemotherapy; Polymorphisms; Progression-free survival; Toxicity