title: Inherited variation in the ATP-binding cassette transporter ABCB1 and survival after chemotherapy for stage III-IV lung cancer.
abstract: BACKGROUND
  The ATP-binding cassette transporter gene ABCB1 and the glutathione S-transferase gene GSTP1 code for a multidrug resistance protein and for a detoxifying phase II metabolic enzyme, respectively, with substrate specificities that include chemotherapy drugs often used to treat lung cancer.
  
  
  METHODS
  We genotyped 11 ABCB1 and eight GSTP1 single nucleotide polymorphisms (SNPs) in 698 white lung cancer patients (all current or former cigarette smokers) and used log-rank test statistics and proportional hazards regression to evaluate associations between SNP genotype and survival.
  
  
  RESULTS
  Using data from all 698 cases, one SNP in ABCB1 (rs2235013) was statistically significantly associated with overall survival (p = 0.038, log-rank test). Chemotherapy and stage jointly (p = 0.025) significantly modified the association between rs2235013 and survival, with statistically significant (p = 0.013, log-rank test) association observed in the subgroup of stage III to IV lung cancer patients who received chemotherapy as part of their first course of treatment (n = 160; 93.1% nonsmall cell). Patients who inherited the minor T allele at ABCB1 rs2235013 experienced better overall survival and recurrence-free survival (hazard ratio, per minor T allele, [95% confidence interval]: 0.66 [0.49-0.90] and 0.55 [0.31-0.95], respectively; adjusted for year of diagnosis, sex, age at diagnosis, cigarette pack years, and stage). In addition, in the advanced stage chemotherapy-treated subgroup, four ABCB1 SNPs (rs6949448, rs2235046, rs1128503, and rs10276036) in mutual high linkage disequilibrium with rs2235013 and an independent ABCB1 SNP (rs1045642) showed statistically significant association (p < 0.05) with survival.
  
  
  CONCLUSIONS
  Inherited variation in ABCB1 may affect survival specifically in advanced stage lung cancer patients who receive chemotherapy.
authors.affiliation: *University of Pittsburgh Cancer Institute and †Department of Epidemiology, University of Pittsburgh Graduate School of Public Health; ‡Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine; §Department of Medicine, University of Pittsburgh School of Medicine; ‖Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine; ¶Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Joel L
authors.initials: JL
authors.lastname: Weissfeld
authors.forename: Brenda
authors.initials: B
authors.lastname: Diergaarde
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nukui
authors.forename: Shama
authors.initials: S
authors.lastname: Buch
authors.forename: Arjun
authors.initials: A
authors.lastname: Pennathur
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
authors.forename: Marjorie
authors.initials: M
authors.lastname: Romkes
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010414:Pennsylvania / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm