MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.

Difan Zheng,Hongbin Ji,Ting Ye,Yihua Sun,Yuan Li,Haiquan Chen,Su Yu,Rui Wang,Haichuan Hu,Xuxia Shen

doi:10.18632/oncotarget.9541

Abstract

PurposeRecurrent MET exon 14 splicing has been revealed in lung cancers and is a promising therapeutic target. Because we have limited knowledge about the natural history of MET mutant tumors, the current study was aiming to determine the clinical and pathological characteristics in non-small cell lung cancers (NSCLC).ResultsTwenty-three patients (1.3%) were positive for MET exon 14 skipping. Patients with MET exon 14 skipping displayed unique characteristics: female, non-smokers, earlier pathology stage and older age. MET exon 14 skipping indicated an early event as other drivers in lung cancer, while MET copy number gain was more likely a late event in lung cancer. Overall survival (OS) of patients harboring MET exon 14 skipping was longer than patients with KRAS mutation. Almost four-fifths of the lung tumors with MET exon 14 skipping had EGFR and/or HER2 gene copy number gains. EGFR inhibitor showed moderate antitumor activity in treatment of a patient harboring MET exon 14 skipping.Patients and MethodsFrom October 2007 to June 2013, we screened 1770 patients with NSCLC and correlated MET status with clinical pathologic characteristics and mutations in EGFR, KRAS, BRAF, HER2, and ALK. Quantitative Real-Time PCR was used to detect MET gene copy number gain. Immunohistochemistry (IHC) was also performed to screen MET exon 14 skipping. Clinicopathological characteristics and survival information were analyzed.ConclusionsMET exon 14 skipping was detected in 1.3% (23/1770) of the Chinese patients with NSCLC. MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC.

Highlights

Lung cancer is the leading cause of cancer deaths worldwide
MET exon 14 skipping indicated an early event as other drivers in lung cancer, while MET copy number gain was more likely a late event in lung cancer
Overall survival (OS) of patients harboring MET exon 14 skipping was longer than patients with KRAS mutation

Summary

Introduction

Lung cancer is the leading cause of cancer deaths worldwide. Non–small cell lung cancer (NSCLC) comprises over 80% of all lung tumors. With better understanding of the major genetic alterations and signaling pathways involved of lung cancer, it has been classified into various subsets with different molecular and clinicopathologic characteristics [1]. Target-based therapeutics designed to specific molecular clusters have revolutionized lung cancer treatment. The most representative examples are gefitinib/erlotinib and crizotinib for lung adenocarcinomas harboring EGFR mutations and ALK/ROS1 fusion, respectively [2, 3]. There remains 20%–40% of lung adenocarcinoma and 80% of lung squamous cell carcinoma without any known targetable oncogenic mutations [4,5,6,7]

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