title: MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression.
abstract: OBJECTIVE
  Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations.
  
  
  METHODS
  We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available.
  
  
  RESULTS
  MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14-mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14-mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14-mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14-wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib.
  
  
  CONCLUSIONS
  MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA. mark_awad@dfci.harvard.edu.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Oxnard
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: David M
authors.initials: DM
authors.lastname: Jackman
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Savukoski
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Dimity
authors.initials: D
authors.lastname: Hall
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Shivdasani
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Heng
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Suman
authors.initials: S
authors.lastname: Verma
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met