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Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer

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Abstract

Purpose

Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery.

Methods and patients

157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined.

Results

METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification.

Conclusions

MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies.

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Acknowledgements

This work was supported by several Spanish grants: SAF2014-54571-R, co-funded by FEDER funds/European Regional Development Fund (ERDF)-“a Way to Build Europe” (to M Sanchez-Cespedes); AGAUR, Agency to Grups de recerca consolidats (2014SGR641) (to M Sanchez-Cespedes); Fondo de Investigaciones Sanitarias (PI14/01109 to E. Nadal); and the Fundación Científica Asociación Española Contra el Cáncer-GCB14-2170.

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Authors and Affiliations

  1. Cancer Epigenetics and Biology Program (PEBC), Genes and Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, 08908, Barcelona, Spain

    M. Saigi, E. Pros & M. Sanchez-Cespedes

  2. Département d’Anatomie et Cytologie Pathologiques, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble and Université Grenoble Alpes, Grenoble, France

    A. McLeer-Florin & E. Brambilla

  3. Department of Medical Oncology, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain

    E. Nadal

  4. OncoBell Program, Clinical Research in Solid Tumors (CReST) Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain

    E. Nadal

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  1. M. Saigi
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  2. A. McLeer-Florin
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  3. E. Pros
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  4. E. Nadal
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  5. E. Brambilla
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  6. M. Sanchez-Cespedes
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Correspondence to M. Sanchez-Cespedes.

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Informed consent was obtained from all individual participants included in the study.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Saigi, M., McLeer-Florin, A., Pros, E. et al. Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer. Clin Transl Oncol 20, 881–888 (2018). https://doi.org/10.1007/s12094-017-1799-7

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  • DOI: https://doi.org/10.1007/s12094-017-1799-7

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