Plasminogen activator inhibitor type 1 (PAI-1) A15T gene polymorphism is associated with prognosis in patients with EGFR mutation positive pulmonary adenocarcinoma

Abstract

Backgroud: Plasminogen activator inhibitor type 1 (PAI-1), the important regulator of plasminogen activator system which controls degradation of extracellular membrane and progression of tumor cells, and PAI-1 gene polymorphic variants have been known as the prognostic biomarkers of non-small cell lung cancer (NSCLC) patients. Recently, experimental in vitro study revealed that transforming growth factor-β1 (TGF-β1) initiated PAI-1 transcription through epithelial growth factor receptor (EGFR) signaling pathway. However, there is a little clinical evidence about the association between the PAI-1 A15T gene polymorphism and prognosis of Korean population with pulmonary adenocarcinoma and the influence of activating mutation of EGFR kinase domain. Methods: We retrospectively reviewed the medical records of 171 patients who were diagnosed with pulmonary adenocarcinoma and underwent EGFR mutation analysis from 1995 through 2009. PAI-1 A15T genetic polymorphism were genotyped by using minisequencing assay. Activating mutation of EGFR kinase domain was confirmed by nucleotide sequencing using nested polymerase chain reaction (PCR) amplification of individual exons (exons 18-21).Results: In all patients with pulmonary adenocarcinoma, there was not significant association between PAI-1 A15T polymorphic variants and prognosis of patients with pulmonary adenocarcinoma in overall survival. However, further subgroup analysis showed that group with the AG/AA genotype had shorter 3-year survival time than group with the GG genotype in patients with EGFR mutant-type pulmonary adenocarcinoma (mean survival time 24.9 vs 32.5 months, respectively, p = 0.015). In multivariate analysis of 3-year survival for patients with pulmonary adenocarcinoma harboring mutant-type EGFR, the AG/GG genotype carriers had poorer prognosis than the GG genotype carriers (HR 8.412, 95% CI: 2.114-33.482, P = 0.003).Conclusion: According to our study with Korean population, the AG/AA genotype of PAI-1 A15T would be a significant predictor of poor short-term survival in patients with pulmonary adenocarcinoma harboring mutant-type EGFR.