title: Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
abstract: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.
  
  
  CONCLUSIONS
  Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts. gframpton@foundationmedicine.com.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California.
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authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Bauer
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
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authors.affiliation: Michiana Hematology-Oncology, PC, Mishawaka, Indiana.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Bufill
authors.affiliation: University of North Carolina School of Medicine, Clinical Research, Thoracic Oncology Program, Chapel Hill, North Carolina.
authors.forename: Carrie
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authors.lastname: Lee
authors.affiliation: South Bend Medical Foundation, South Bend, Indiana.
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authors.affiliation: South Bend Medical Foundation, South Bend, Indiana.
authors.forename: Rick
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authors.lastname: Hoover
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Irvine, California.
authors.forename: Sai-Hong Ignatius
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authors.lastname: Ou
authors.affiliation: The University of Chicago School of Medicine, Chicago, Illinois.
authors.forename: Ravi
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authors.lastname: Salgia
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Tim
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authors.lastname: Brennan
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Chalmers
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Savina
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authors.lastname: Jaeger
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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authors.initials: A
authors.lastname: Huang
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Rachel
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authors.lastname: Erlich
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.initials: A
authors.lastname: Fichtenholtz
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.initials: KA
authors.lastname: Gowen
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Joel
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authors.lastname: Greenbowe
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Adrienne
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authors.lastname: Johnson
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Depinder
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authors.lastname: Khaira
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Caitlin
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authors.lastname: McMahon
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sanford
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Roels
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Jared
authors.initials: J
authors.lastname: White
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Collisson
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Malte
authors.initials: M
authors.lastname: Peters
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts.
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authors.initials: VA
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mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met