title: MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC).
abstract: OBJECTIVE
  We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation.
  
  
  METHODS
  Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation.
  
  
  RESULTS
  Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25-50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively).
  
  
  CONCLUSIONS
  MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation.
authors.affiliation: Servei d'Oncologia Mèdica, Hospital del Mar, Barcelona, Spain.|Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Casadevall
authors.affiliation: Servei de Patologia, Hospital del Mar, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gimeno
authors.affiliation: Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Clavé
authors.affiliation: Servei d'Oncologia Mèdica, Hospital del Mar, Barcelona, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Taus
authors.affiliation: Servei de Patologia, Hospital del Mar, Barcelona, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Pijuan
authors.affiliation: Servei d'Oncologia Mèdica, Hospital del Mar, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Arumí
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Lorenzo
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Menéndez
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Cañadas
authors.affiliation: Servei d'Oncologia Mèdica, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Servei de Patologia, Hospital del Mar, Barcelona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Serrano
authors.affiliation: Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Espinet
authors.affiliation: Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Salido
authors.affiliation: Servei d'Oncologia Mèdica, Hospital del Mar, Barcelona, Spain.|Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Edurne
authors.initials: E
authors.lastname: Arriola
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: FISH; c-MET; heterogeneity; immunohistochemistry; non-small-cell lung cancer