title: MET amplification status in therapy-naïve adeno- and squamous cell carcinomas of the lung.
abstract: OBJECTIVE
  MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer.
  
  
  METHODS
  We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC.
  
  
  RESULTS
  Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations.
  
  
  CONCLUSIONS
  MET amplification is not a mutually exclusive genetic event in therapy-naïve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors.
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Institute of Pathology, University Hospital Göttingen, Göttingen, Germany. hans-ulrich.schildhaus@med.uni-goettingen.de.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
authors.affiliation: Institute of Pathology Nordhessen, Kassel, Germany. Targos Molecular Pathology, Kassel, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Binot
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Merkelbach-Bruse
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Fassunke
authors.affiliation: Thoraxzentrum im Malteser Krankenhaus Bonn/Rhein-Sieg, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schulte
authors.affiliation: Johanniter-Krankenhaus, Evangelische Kliniken Bonn GmbH, Bonn, Germany.
authors.forename: Yon-Dschun
authors.initials: YD
authors.lastname: Ko
authors.affiliation: Evangelisches Krankenhaus Kalk, Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlesinger
authors.affiliation: Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Bos
authors.affiliation: Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany.
authors.forename: Masyar
authors.initials: M
authors.lastname: Gardizi
authors.affiliation: Lungenklinik Merheim, Kliniken der Stadt Köln GmbH, Cologne, Germany.
authors.forename: Walburga
authors.initials: W
authors.lastname: Engel-Riedel
authors.affiliation: Institute of Pathology, Kliniken der Stadt Köln GmbH, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brockmann
authors.affiliation: Lungenklinik Hemer, Hemer, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Serke
authors.affiliation: Thoraxzentrum im Malteser Krankenhaus Bonn/Rhein-Sieg, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gerigk
authors.affiliation: Department of Cardiothoracic Surgery, University of Cologne, Cologne, Germany.
authors.forename: Khosro
authors.initials: K
authors.lastname: Hekmat
authors.affiliation: Department III of Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Konrad F
authors.initials: KF
authors.lastname: Frank
authors.affiliation: PIOH-Praxis Internistischer Onkologie und Hämatologie Köln, Cologne, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Reiser
authors.affiliation: PIOH-Praxis Internistischer Onkologie und Hämatologie Frechen, Frechen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.affiliation: Florence Nightingale Krankenhaus Düsseldorf Kaiserswerth, Düsseldorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krüger
authors.affiliation: Lungenklinik Merheim, Kliniken der Stadt Köln GmbH, Cologne, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Stoelben
authors.affiliation: Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany. NGM, Network Genomic Medicine and GCGC, Gastrointestinal Cancer Group Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.affiliation: Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Department I of Internal Medicine and Centre of Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany. Targos Molecular Pathology, Kassel, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met