MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis

Purpose: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naive non-small cell lung carcinoma (NSCLC). Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (MET Delta 14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively. Results: MET Delta 14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. MET Delta 14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). MET Delta 14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio 5) was mutually exclusive to the major driver genes except MET Delta 14. Oncogenic MET Delta 14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. MET Delta 14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both MET Delta 14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis. Conclusions: The high incidence of MET Delta 14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. (C) 2016 AACR.