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

Author information

Affiliations

  • 1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
      Authors
    • Tong JH 1
    • Yeung SF 1
    • Chan AW 1
    • Chung LY 1
    • Chau SL 1
    • Lung RW 1
    • Tong CY 1
    • Chow C 1
    • Tin EK 1
    • Yu YH 1
    • Li H 1
    • Pan Y 1
    • Chak WP 1
    • To KF 1
    (14 authors)
  • 2. Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong.
      Authors
    • Ng CS 2
    (1 author)
  • 3. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong.
      Authors
    • Mok TS 3
    (1 author)

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Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 04 Feb 2016, 22(12):3048-3056
https://doi.org/10.1158/1078-0432.ccr-15-2061 PMID: 26847053 

A comment on this article appears in "MET DNA Alterations in NSCLC-Letter." Clin Cancer Res. 2016 Jul 15;22(14):3697-8. A comment on this article appears in "MET DNA Alterations in NSCLC-Reply." Clin Cancer Res. 2016 Jul 15;22(14):3699.

Abstract 

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 AACRSee related commentary by Drilon, p. 2832.

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Read article at publisher's site: https://doi.org/10.1158/1078-0432.ccr-15-2061

Read article for free, from open access legal sources, via Unpaywall: https://clincancerres.aacrjournals.org/content/clincanres/22/12/3048.full.pdfUnpaywall

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