PIK3CA Mutations Frequently Coexist with EGFR/KRAS Mutations in Non-Small Cell Lung Cancer and Suggest Poor Prognosis in EGFR/KRAS Wildtype Subgroup

Lei Wang,Haiquan Chen,Yihua Sun,Lei Shen,Yongfu Yu,Yuan Li,Hang Li,Deng Cai,Rui Wang,Haichuan Hu,Yunjian Pan,Giuseppe Viglietto

doi:10.1371/journal.pone.0088291

Lei Wang, Haiquan Chen + Show 10 more

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https://doi.org/10.1371/journal.pone.0088291

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Journal: PloS one	Publication Date: Feb 12, 2014
Citations: 143	License type: CC BY 4.0

Affiliation: Fudan University Shanghai Cancer Center, Fudan University

Abstract

Purpose PIK3CA gene encoding a catalytic subunit of the phosphatidylinositol-3-kinase (PI3K) is mutated and/or amplified in various neoplasia, including lung cancer. Here we investigated PIK3CA gene alterations, the expression of core components of PI3K pathway, and evaluated their clinical importance in non-small cell lung cancer (NSCLC).Materials and methodsOncogenic mutations/rearrangements in PIK3CA, EGFR, KRAS, HER2, BRAF, AKT1 and ALK genes were detected in tumors from 1117 patients with NSCLC. PIK3CA gene copy number was examined by fluorescent in situ hybridization and the expression of PI3K p110 subunit alpha (PI3K p110α), p-Akt, mTOR, PTEN was determined by immunohistochemistry in PIK3CA mutant cases and 108 patients without PIK3CA mutation.Results PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma. Among 34 PIK3CA mutant cases, 17 tumors harbored concurrent EGFR mutations and 4 had KRAS mutations. PIK3CA mutation was significantly associated with high expression of PI3K p110α (p<0.0001), p-Akt (p = 0.024) and mTOR (p = 0.001), but not correlated with PIK3CA amplification (p = 0.463). Patients with single PIK3CA mutation had shorter overall survival than those with PIK3CA-EGFR/KRAS co-mutation or wildtype PIK3CA (p = 0.004). A significantly worse survival was also found in patients with PIK3CA mutations than those without PIK3CA mutations in the EGFR/KRAS wildtype subgroup (p = 0.043)Conclusions PIK3CA mutations frequently coexist with EGFR/KRAS mutations. The poor prognosis of patients with single PIK3CA mutation in NSCLC and the prognostic value of PIK3CA mutation in EGFR/KRAS wildtype subgroup suggest the distinct mutation status of PIK3CA gene should be determined for individual therapeutic strategies in NSCLC.

Highlights

It has been well established that the phosphatidylinositol-3kinase (PI3K) pathway is related to carcinogenesis in a variety of human cancers [1,2,3]
PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma
PIK3CA mutations frequently coexist with EGFR/KRAS mutations

Summary

Introduction

It has been well established that the phosphatidylinositol-3kinase (PI3K) pathway is related to carcinogenesis in a variety of human cancers [1,2,3]. PI3K initiates events leading to phosphorylation of Akt, which affects additional downstream signaling proteins involved in cell growth, metabolism, proliferation, survival, motility, and invasion [4,5,6]. PI3Kdependent activity is frequently elevated due to mutation of PIK3CA, a gene encoding the p110a catalytic subunit of PI3K (PI3K p110a), and the absence of the phosphatase and tensin homolog(PTEN) protein, a tumor suppressor with an important role in regulating the PI3K antiapoptotic and survival pathway [7,8]. Multiple mutations of PIK3CA that occur with regularity and in highly conserved regions of the gene lead to amino acid substitutions in the helical binding domain encoded by exon 9 and in the catalytic subunit of p110a encoded by exon 20, which result in upregulating PI3K pathway signaling [10]. Akt and mTOR lie downstream of PI3K and increased mTOR phosphorylation is frequently observed alongside with activated Akt in NSCLC and dysregulation of mTOR contributes to lung cancer progression [15,16]

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