EGFR variant III act as the major determinant factors in the EGFR/PI3K/AKT pathway for the survival outcome of oral cancer patients

[[abstract]]Background: Activation of the EGFR/PI3K/AKT pathway is known for the crucial role in tumorigenesis of oral cancer. Our study focused to analyze the aberrations of the regulatory factors which lead to over-activation of this pathway. Patients and methods: A series of studies was conducted with application of the archival oral cancer tissue specimens which was obtained from patients who received surgical resection. For the factors in interest, we studied their protein expression and gene copy number (GCN) by immunohistochemical staining and real-time polymerase chain reaction, respectively. Statistical assessment was then arranged to determine their association and the impact to survival outcomes. Results: In the total108 samples examined, the activation of AKT was evidenced in 86.9% by identification of the cytoplasmic phosphorylated AKT (pAKT). There were 63.9% of the samples with expression of membranous wild-type EGFR, and 49.1% of the samples with undetectable PTEN in the tumor tissue. Judgment of EGFR variant III (EGFRvIII) showed that 75.0% of the samples were positive, with 38.5% low expression and the remaining 31.5% high expression. Studies of the PIK3CA gene revealed alteration of GCN in 24.8% of the samples and hotspot point mutation in 2.3% of the samples. Those of the EGFR gene showed evidence of GCN amplification in 49.0% of the samples, and were in association to expression of the wild-type protein but not EGFRvIII. Further analysis of EGFRvIII negative/low or high expression was in correlation to the T classification and the disease stage. For the survival analyses, classification according to pAKT or EGFRvIII both led to significantly different Kaplan-Meier curves. Moreover, simultaneous judgment by the status of EGFR wild type and variant III also served to predict the patient survival. By the multivariate analysis, individual factors such as pAKT, EGFRvIII and the disease stage were further suggested as the determinants of the survival outcome. Conclusions: Our investigation showed that in oral cancers, aberrations in the regulatory factors of the AKT pathway were frequent. Expression of EGFRvIII and pAKT were negative predictors for the patient survival