SNPs in the transforming growth factor beta pathway as predictors of outcome in advanced lung adenocarcinoma with EGFR mutations treated with Gefitinib
Menée à partir d'échantillons tumoraux prélevés sur 206 patients atteints d'un adénocarcinome du poumon de stade avancé, cette étude évalue l'association entre 33 polymorphismes à simple nucléotide de 13 gènes impliqués dans la voie de signalisation du facteur de croissance TGF-bêta et la survie chez les patients présentant des mutations du gène EGFR et traités par géfitinib
Background : The aim of this study was to evaluate whether genetic variations in the transforming growth factor beta (TGF-
β) pathway influenced clinical outcome of advanced lung ademocarcinoma with EGFR mutations treated with gefitinib.
Patients and 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 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 performed to assess the role of biological/clinical parameters in progression-free survival (PFS) and overall survival (OS) using Pearson's χ2 test, log-rank test and Cox proportional hazards model.
Results
:
Among SNPs analyzed, multivariate analysis showed the 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 months vs. 17.5 months; Log-rank P=0.020; and 20.8 months vs. 9.4 months; Log-rank P=0.001), as compared with patients with wild-type EGFR tumors. In patients with mutant EGFR, the CT genotype of SMAD3: rs11071938 and the CC genotype of SMAD3: rs6494633 were also found to be associated with better PFS. Dual luciferase reporter assays showed gefitinib-resistant PC9/G cells transfeted with SMAD3: rs11632964T allelic reporter construct showed significantly lower luciferase activities compared to 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 ademocarcinoma after gefitinib treatment, especially in those with EGFR mutations.
Annals of Oncology , résumé, 2014