title: High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta™ Panel: exploring therapeutic targets.
abstract: BACKGROUND
  Pulmonary sarcomatoid carcinomas (SC) are tumors characterized by poor prognosis and resistance to conventional platinum-based chemotherapy. This study sought to describe the mutational profile of SC using high-throughput genotyping technology.
  
  
  METHODS
  We used mass spectrometry to test 114 surgical biopsies from 81 patients with SC for 214 mutations affecting 26 oncogenes and tumor suppressor genes.
  
  
  RESULTS
  In total, 75 (92.6%) patients were smokers. Within the total 81 tumors, 67 distinct somatic alterations were identified, with 56 tumors (69.1%) harboring at least one mutation. The most frequent mutations were KRAS (27.2%), EGFR (22.2%), TP53 (22.2%), STK11 (7.4%), NOTCH1 (4.9%), NRAS (4.9%), and PI3KCA (4.9%). The EGFR mutations were almost always rare mutations (89%). In 32 tumors (39.5%), two or more mutations co-existed, with up to four mutations in a single case. In six different cases, comparative genetic analysis of different histological areas from the same tumor (giant, spindle, or epithelial component) revealed a 61% concordance rate for all the mutations with a 10% detection threshold, compared with 91.7% with a 20% detection threshold.
  
  
  CONCLUSIONS
  Our results demonstrated a high mutation rate and frequent co-mutations. Despite SC tumors exhibiting a high histological heterogeneity, some intratumoral molecular homogeneity was found. Now with newly developed targeted therapies, SC patients may be eligible for new target mutations, and can now therefore be screened for clinical trials.
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris.
authors.forename: V
authors.initials: V
authors.lastname: Fallet
authors.affiliation: INSERM U1004, Université de Paris 11, Institut André Wolf, Villejuif Department of Biochemistry and Molecular Biology, AP-HP, Hôpital Paul Brousse, Villejuif.
authors.forename: R
authors.initials: R
authors.lastname: Saffroy
authors.affiliation: Pulmonary Medicine Unit, Hôpital Louis Pradel, Hospices Civils, Lyon.
authors.forename: N
authors.initials: N
authors.lastname: Girard
authors.affiliation: Pulmonary Medicine Unit, Hôpital Larrey, Centre Hospitalier Universitaire, Université de Toulouse III, Toulouse.
authors.forename: J
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Department of Pathology, Hôpital A. Michallon, Centre Hospitalier Universitaire, Grenoble.
authors.forename: S
authors.initials: S
authors.lastname: Lantuejoul
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris.
authors.forename: T
authors.initials: T
authors.lastname: Vieira
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Rangueil, Toulouse.
authors.forename: I
authors.initials: I
authors.lastname: Rouquette
authors.affiliation: Department of Pathology, Hôpital Louis Pradel, Lyon.
authors.forename: F
authors.initials: F
authors.lastname: Thivolet-Bejui
authors.affiliation: Pulmonary Medicine Unit, Hôpital Larrey, Centre Hospitalier Universitaire, Université de Toulouse III, Toulouse.
authors.forename: M
authors.initials: M
authors.lastname: Ung
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris.
authors.forename: V
authors.initials: V
authors.lastname: Poulot
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris.
authors.forename: L
authors.initials: L
authors.lastname: Schlick
authors.affiliation: Pulmonary Medicine Unit, Hôpital A. Michallon, Centre Hospitalier Universitaire, Grenoble.
authors.forename: D
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris Department of Pathology, AP-HP, Hôpital Tenon, Paris.
authors.forename: M
authors.initials: M
authors.lastname: Antoine
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris Pulmonary Medicine Unit, AP-HP, Hôpital Tenon, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: INSERM U1004, Université de Paris 11, Institut André Wolf, Villejuif Department of Biochemistry and Molecular Biology, AP-HP, Hôpital Paul Brousse, Villejuif.
authors.forename: A
authors.initials: A
authors.lastname: Lemoine
authors.affiliation: GRC n°04, Theranoscan, Sorbonne Universités, UPMC Université de Paris 06, Paris Pulmonary Medicine Unit, AP-HP, Hôpital Tenon, Paris, France marie.wislez@tnn.aphp.fr.
authors.forename: M
authors.initials: M
authors.lastname: Wislez
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics; D018286:Carcinoma, Giant Cell / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002296:Carcinosarcoma / Q000235:genetics*; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D012189:Retrospective Studies; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D051881:Receptor, Notch1; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EGFR; KRAS; lung sarcomatoid carcinoma; mutation; nonsmall-cell lung cancer