MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis
| Autor: | Chit Chow, Yau H. Yu, Anthony W.H. Chan, Hui Li, Yi Pan, Shuk L. Chau, Sai F. Yeung, Calvin S.H. Ng, Carol Y.K. Tong, Raymond W.M. Lung, Edith K. Y. Tin, Joanna H.M. Tong, Wing Po Chak, Ka F. To, Tony Mok, Lau Y. Chung |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Cancer Research Lung Neoplasms DNA Copy Number Variations Adenosquamous carcinoma Gene Dosage Biology 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Carcinoma medicine Humans Sarcomatoid carcinoma Aged Aged 80 and over Splice site mutation Large cell Cancer Middle Aged Proto-Oncogene Proteins c-met Prognosis medicine.disease MET Exon 14 Skipping Mutation 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Cancer research Adenocarcinoma Female RNA Splice Sites |
| Zdroj: | Clinical Cancer Research. 22:3048-3056 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-15-2061 |
| Popis: | 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-naïve non–small cell lung carcinoma (NSCLC). Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively. Results: METΔ14 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. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 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 METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis. Conclusions: The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048–56. ©2016 AACR. See related commentary by Drilon, p. 2832 |
| Databáze: | OpenAIRE |
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