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

// Difan Zheng 1, 2, * , Rui Wang 1, 2, * , Ting Ye 1, 2, * , Su Yu 1, 2, 5 , Haichuan Hu 1, 2, 7 , Xuxia Shen 2, 3 , Yuan Li 2, 3 , Hongbin Ji 6, * , Yihua Sun 1, 2, * , Haiquan Chen 1, 2, 4, * 1 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China 4 Institutes of Biomedical Sciences, Fudan University, Shanghai, China 5 Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China 6 Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China 7 Massachusetts General Hospital Cancer Center, Boston, MA, USA * These authors contributed equally to this work Correspondence to: Haiquan Chen, email: hqchen1@yahoo.com Yihua Sun, email: Sun_yihua76@hotmail.com Keywords: MET, non-small cell lung cancer, surgery, targeted therapy Received: November 10, 2015      Accepted: April 08, 2016      Published: May 21, 2016 ABSTRACT Purpose: Recurrent 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). Results: Twenty-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 Methods: From 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. Conclusions: MET 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.