title: Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.
abstract: BACKGROUND
  Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).
  
  
  METHODS
  To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
  
  
  RESULTS
  SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
  
  
  CONCLUSIONS
  These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1340, Houston, TX 77030, USA. xwu@mdanderson.org
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Shama C
authors.initials: SC
authors.lastname: Buch
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nukui
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ramirez Serrano
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
authors.forename: Adrian
authors.initials: A
authors.lastname: Cassidy
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Chang
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Marjorie
authors.initials: M
authors.lastname: Romkes
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012372:ROC Curve; D018714:Radiotherapy, Adjuvant; D019707:Receptors, Chemokine / Q000235:genetics*; D015203:Reproducibility of Results; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: C102741:CMKLR1 protein, human; D009944:Organoplatinum Compounds; D019707:Receptors, Chemokine