Immunohistochemical characterization of the mTOR pathway in stage-I non-small-cell lung carcinoma.

Abstract

Dysregulation of mammalian target of rapamycin (mTOR) pathway has been linked with malignant tumorigenesis. This study explored the expression profiles of proteins involved in the mTOR pathway and their relationships with clinicopathologic characteristics in stage-I non-small-cell lung carcinoma (NSCLC). The protein expression profiles of PTEN, p-Akt, p-mTOR, p-S6, and eIF4E were examined using immunohistochemical staining and tissue microarray method in 408 patients with stage-I NSCLC (250 adenocarcinomas [ADC] and 158 squamous cell carcinomas). Retained PTEN expression (P<0.001), p-mTOR expression (P<0.001), and p-S6 expression (P=0.007) were associated with ADC histology. Expression of PTEN (P=0.001), p-Akt (P=0.005), p-mTOR (P=0.007), p-S6 (P<0.001) were correlated with lower pathologic T stage. PTEN loss was correlated with male gender and smoking history and p-mTOR expression was inversely correlated with these factors (P<0.001). Subgroup analysis of ADCs indicated that male gender, high pT stage, lymphovascular invasion, and PTEN loss were poor prognostic factors. Multivariate analysis revealed that the PTEN(-)/p-Akt(+)/p-mTOR(+) combination more effectively determined the prognosis of ADC (hazard ratio=2.2, P=0.004) than PTEN alone. Activation of the mTOR pathway in early-stage ADCs suggests a significant role for the mTOR axis in early carcinogenesis. The combination of PTEN(-)/p-Akt(+)/p-mTOR(+) expression was correlated with poor overall survival in patients with stage-I lung ADC.