MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC)
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David Casadevall1,6,*, Javier Gimeno2,*, Sergi Clavé3,4,*, Álvaro Taus1, Lara Pijuan2, Miriam Arumí1, Marta Lorenzo4, Silvia Menéndez4, Israel Cañadas4, Joan Albanell1,4,5, Sergio Serrano2, Blanca Espinet3,4, Marta Salido3,4, Edurne Arriola1,4,#
1Servei d’Oncologia Mèdica, Hospital del Mar, Barcelona, Spain
2Servei de Patologia, Hospital del Mar, Barcelona, Spain
3Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain
4Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
5Universitat Pompeu Fabra, Barcelona, Spain
6Universitat Autònoma de Barcelona, Bellaterra, Spain
#Cancer Sciences Unit, University of Southampton, Southampton, UK
*These authors have contributed equally to this work
David Casadevall, e-mail: firstname.lastname@example.org
Keywords: c-MET, immunohistochemistry, FISH, non-small-cell lung cancer, heterogeneity
Received: February 25, 2015 Accepted: May 05, 2015 Published: May 15, 2015
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.
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