MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer
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Difan Zheng1,2,*, Rui Wang1,2,*, Ting Ye1,2,*, Su Yu1,2,5, Haichuan Hu1,2,7, Xuxia Shen2,3, Yuan Li2,3, Hongbin Ji6,*, Yihua Sun1,2,*, Haiquan Chen1,2,4,*
1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
4Institutes of Biomedical Sciences, Fudan University, Shanghai, China
5Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
6Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China
7Massachusetts General Hospital Cancer Center, Boston, MA, USA
*These authors contributed equally to this work
Haiquan Chen, email: [email protected]
Yihua Sun, email: [email protected]
Keywords: MET, non-small cell lung cancer, surgery, targeted therapy
Received: November 10, 2015 Accepted: April 08, 2016 Published: May 21, 2016
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.
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