title: Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors.
abstract: BACKGROUND
  To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT.
  
  
  METHODS
  Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features.
  
  
  RESULTS
  Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E).
  
  
  CONCLUSIONS
  All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.
authors.affiliation: Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena.
authors.forename: L
authors.initials: L
authors.lastname: Schirosi
authors.affiliation: Department of Diagnostic Medical Sciences and Special Therapies, Special Pathological Anatomy Section, University of Padua Medical School, Padova.
authors.forename: N
authors.initials: N
authors.lastname: Nannini
authors.affiliation: Laboratory of Molecular Biology, Hospital St. Maria Nuova, Reggio Emilia.
authors.forename: D
authors.initials: D
authors.lastname: Nicoli
authors.affiliation: Section of Pathologic Anatomy, Hospital St. Maria Nuova, Reggio Emilia.
authors.forename: A
authors.initials: A
authors.lastname: Cavazza
authors.affiliation: Section of Pathologic Anatomy, Hospital St. Maria Nuova, Reggio Emilia.
authors.forename: R
authors.initials: R
authors.lastname: Valli
authors.affiliation: Oncology Division, Hospital of Cremona, Cremona.
authors.forename: S
authors.initials: S
authors.lastname: Buti
authors.affiliation: Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena.
authors.forename: L
authors.initials: L
authors.lastname: Garagnani
authors.affiliation: Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena.
authors.forename: G
authors.initials: G
authors.lastname: Sartori
authors.affiliation: Department of Diagnostic Medical Sciences and Special Therapies, Special Pathological Anatomy Section, University of Padua Medical School, Padova.
authors.forename: F
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Center of Predictive Molecular Medicine, Center of Excellence on Aging, University of Chieti, Chieti.
authors.forename: A
authors.initials: A
authors.lastname: Marchetti
authors.affiliation: Center of Predictive Molecular Medicine, Center of Excellence on Aging, University of Chieti, Chieti.
authors.forename: F
authors.initials: F
authors.lastname: Buttitta
authors.affiliation: Center of Predictive Molecular Medicine, Center of Excellence on Aging, University of Chieti, Chieti.
authors.forename: L
authors.initials: L
authors.lastname: Felicioni
authors.affiliation: Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena.
authors.forename: M
authors.initials: M
authors.lastname: Migaldi
authors.affiliation: Division of Thoracic Surgery, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua Medical School, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rea
authors.affiliation: Division of Thoracic Surgery, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua Medical School, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Di Chiara
authors.affiliation: Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena.
authors.forename: M C
authors.initials: MC
authors.lastname: Mengoli
authors.affiliation: Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena. Electronic address: rossi.giulio@policlinico.mo.it.
authors.forename: G
authors.initials: G
authors.lastname: Rossi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D018956:CD5 Antigens / Q000378:metabolism; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D000077157:Sorafenib; D000077210:Sunitinib; D013945:Thymoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D013953:Thymus Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; D018956:CD5 Antigens; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib