title: SNPs in the transforming growth factor-β pathway as predictors of outcome in advanced lung adenocarcinoma with EGFR mutations treated with gefitinib.
abstract: BACKGROUND
  The aim of this study was to evaluate whether genetic variations in the transforming growth factor-β (TGF-β) pathway influenced clinical outcome of advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations treated with gefitinib.
  
  
  METHODS
  Two hundred six patients with advanced lung adenocarcinomas were enrolled in this study. EGFR mutation in these tumors was detected. Among them, 106 patients with EGFR mutation and 37 of 100 patients with wild type were treated with gefitinib. Genotype of 33 single-nucleotide polymorphisms (SNPs) from 13 genes involved in the TGF-β signaling pathway was determined, and their association with survival time was analyzed. Univariate and multivariate analyses were carried out to assess the role of biological/clinical parameters in progression-free survival (PFS) and overall survival (OS) using Pearson's χ(2) test, log-rank test, and Cox proportional hazards model.
  
  
  RESULTS
  Among SNPs analyzed, multivariate analysis showed the cytidylate and thymidine (CT) genotype of SMAD3: rs11632964 was associated with a longer OS and PFS when the entire cohort of 143 patients were included; the association was significant in the patients with EGFR mutant tumors (30.8 versus 17.5 months; log-rank P = 0.020; and 20.8 versus 9.4 months; log-rank P = 0.001), when compared with patients with wild-type EGFR tumors. In patients with mutant EGFR, the CT genotype of SMAD3: rs11071938 and the cytidylate and cytidylate genotype of SMAD3: rs6494633 were also found to be associated with better PFS. Dual luciferase reporter assays showed gefitinib-resistant PC9/G cells transfected with SMAD3: rs11632964T allelic reporter construct showed significantly lower luciferase activities compared with cells expression C allelic reporter construct. There was significantly decreased expression of SMAD3 and pi-SMAD3 in the PC-9/G cells compared with PC-9.
  
  
  CONCLUSIONS
  Among the candidate genes involved in the TGF-β pathway, the polymorphisms of SMAD3 appear to be highly predictive of outcome of patients with lung adenocarcinoma after gefitinib treatment, especially in those with EGFR mutations.
authors.affiliation: Departments of Oncology.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Departments of Oncology.
authors.forename: Q X
authors.initials: QX
authors.lastname: Li
authors.affiliation: Departments of Oncology.
authors.forename: H L
authors.initials: HL
authors.lastname: Wu
authors.affiliation: Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province.
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.affiliation: College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: Departments of Oncology.
authors.forename: S Y
authors.initials: SY
authors.lastname: Yu
authors.affiliation: Departments of Oncology yxl@medmail.com.cn.
authors.forename: X L
authors.initials: XL
authors.lastname: Yuan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR-TKI; SMAD3; TGF-β; polymorphisms; survival