title: MET gene copy number alterations and expression of MET and hepatocyte growth factor are potential biomarkers in angiosarcomas and undifferentiated pleomorphic sarcomas.
abstract: Soft tissue sarcomas are a heterogeneous group of tumors with many different subtypes. In 2014 an estimated 12,020 newly diagnosed cases and 4,740 soft tissue sarcoma related deaths can be expected in the United States. Many soft tissue sarcomas are associated with poor prognosis and therapeutic options are often limited. The evolution of precision medicine has not yet fully reached the clinical treatment of sarcomas since therapeutically tractable genetic changes have not been comprehensively studied so far. We analyzed a total of 484 adult-type malignant mesenchymal tumors by MET fluorescence in situ hybridization and MET and hepatocyte growth factor immunohistochemistry. Eleven different entities were included, among them the most common and clinically relevant subtypes and tumors with specific translocations or complex genetic changes. MET protein expression was observed in 2.6% of the cases, all of which were either undifferentiated pleomorphic sarcomas or angiosarcomas, showing positivity rates of 14% and 17%, respectively. 6% of the tumors showed hepatocyte growth factor overexpression, mainly seen in undifferentiated pleomorphic sarcomas and angiosarcomas, but also in clear cell sarcomas, malignant peripheral nerve sheath tumors, leiomyosarcomas and gastrointestinal stromal tumors. MET and hepatocyte growth factor overexpression were significantly correlated and may suggest an autocrine activation in these tumors. MET FISH amplification and copy number gain were present in 4% of the tumors (15/413). Two samples, both undifferentiated pleomorphic sarcomas, fulfilled the criteria for high level amplification of MET, one undifferentiated pleomorphic sarcoma reached an intermediate level copy number gain, and 12 samples of different subtypes were categorized as low level copy number gains for MET. Our findings indicate that angiosarcomas and undifferentiated pleomorphic sarcomas rather than other frequent adult-type sarcomas should be enrolled in screening programs for clinical trials with MET inhibitors. The screening methods should include both in situ hybridization and immunohistochemistry.
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany; Institute of Pathology, University Hospital Göttingen, Göttingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Schmitz
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Binot
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Fassunke
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Künstlinger
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Michaela A
authors.initials: MA
authors.lastname: Ihle
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Heydt
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany; Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Merkelbach-Bruse
authors.affiliation: Targos Molecular Pathology GmbH, Kassel, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany; Institute of Pathology, University Hospital Göttingen, Göttingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D005784:Gene Amplification; D018628:Gene Dosage; D006394:Hemangiosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
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