Correlation among genetic variations of c-MET in Chinese patients with non-small cell lung cancer.

Jianchun Duan,Minglei Zhuo,Hua Bai,Jun Zhao,Xiaodan Yang,Zhijie Wang,Tongtong An,Jie Wang

doi:10.18632/oncotarget.23474

Abstract

BackgroundThe purpose of our research was to determine the correlation of amplification, protein expression and somatic mutation of c-MET in IIIb-IV stage NSCLC (Non-small cell lung cancer). We also explored correlation of c-MET variation with clinical outcome.Resultsc-MET expression was observed in 28.6% (56/196) cases, and among those 13.8% (27/196) were shown to be FISH positive. Only 2.67% patients in this study carried the c-MET mutation. Cases with c-MET FISH positive were all IHC positive ,but in IHC positive cases, only half were FISH positive. Among patients with IHC2+ staining, 35.5% was FISH positive, while cases with IHC3+ staining,64% was FISH positive. Both protein expression and copy number of c-MET did not significantly correlate with clinical prognosis in these patients treated with EGFR-TKIs.ConclusionsIHC could be used as a preliminary screening method for c-MET copy number amplification and should be confirmed by FISH only in IHC positive case which facilitate selection of ALK or MET inhibitor therapy.Methodsc-MET gene copy number, protein expression and somatic mutation for exon 14 were detected by fluorescent- In-Situ-Hybridization (FISH), Immunohistochemistry (IHC), and Denaturing-High-Performance-Liquid-Chromatography (DHPLC), respectively, in 196 NSCLC patients. The relationship between c-MET abnormalities and clinical outcome of targeted therapy was analyzed by McNemar's test.

Highlights

The c-MET gene locates on 7q21-31 and encodes a tyrosine kinase [1] Deregulation of HGF/c-MET signaling pathway due to mutation, amplification, overexpression, or activation has been observed in many types of cancers
IHC could be used as a preliminary screening method for c-MET copy number amplification and should be confirmed by fluorescent- In-Situ-Hybridization (FISH) only in IHC positive case which facilitate selection of anaplastic lymphoma kinase gene (ALK) or MET inhibitor therapy
Studies in patients of NSCLC treated with EGFRTKIs, including Iressa or Tarceva, have shown that acquired resistance to EGFR-TKIs due to c-MET overexpression in approximately 20% population [7], which cause PI3K/Akt pathway activity

Summary

Introduction

The c-MET gene locates on 7q21-31 and encodes a tyrosine kinase [1] Deregulation of HGF/c-MET signaling pathway due to mutation, amplification, overexpression, or activation has been observed in many types of cancers. Overexpression of c-MET was found in 25–75% lung cancer patients [2, 3], gene amplification has been observed in 5–22% [2,3,4],and mutations in about 5% of tumors [5, 6]. At present, ongoing phase I/II clinical trials are being carried out with c-MET inhibitors on patients with lung cancer [9, 10], and some of them have shown the effect of inhibiting tumor growth [11]. We explored correlation of c-MET variation with clinical outcome

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