title: Analysis of a panel of druggable gene mutations and of ALK and PD-L1 expression in a series of thymic epithelial tumors (TETs).
abstract: Thymic epithelial tumors (TETs) are rare neoplasms with different prognosis lacking consistent molecular alterations possibly leading to targeted therapy. We collected a consecutive series of TETs aimed at investigating the mutational status of druggable genes (EGFR, c-KIT, KRAS, BRAF, PDGFR-alpha and -beta, HER2 and c-MET) and the expression of ALK and PD-L1.
  
  
  
  One hundred twelve consecutive cases of TETs and relative clinico-pathologic features were collected. Immunohistochemical expression of ALK (clone D5F3) and PD-L1 (clone E1L3N), molecular analysis of EGFR (exons 18-21), c-KIT (exons 9,11,13,14,17), KRAS (exon 2), BRAF (exon 15), PDGFR-alpha (exon 12) and -beta (exons 12, 14, 18), HER-2 (exons 19 and 20) and c-MET (exons 14, 17, 18, 19) mutations were performed. Immuno-molecular results were then statistically matched with clinico-pathologic characteristics.
  
  
  
  Patients were male in 54% of cases, with a median age of 61 years (range 19-83) and affected mainly by thymoma (78%) in stage II (45%). At molecular analysis, there were 4 c-KIT mutations (occurring in exon 11 V559A, L576P, Y553N and exon 17 D820E) in thymic carcinomas (typeC), but not in other tumor types (p=0.003). No mutations were detected in other genes and none case was ALK positive. Twenty-nine (26%) cases were PD-L1 positive (65% of thymic carcinomas and 18% of thymomas). High PD-L1 expression was statistically associated with WHO classification stage type C (p<0.001) and Masaoka stage III-IV disease (p=0.007). In univariate analysis, WHO classification type C, advanced Masaoka stage and absence of myasthenia, but not PD-L1 expressions were correlated with worse survival; at multivariate analysis, only WHO type C confirmed its negative prognostic role.
  
  
  
  A subset of TETs as thymic carcinomas can harbor c-KIT mutations and elevated PD-L1 expression that could represent targets of potential therapeutic use.
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy. Electronic address: mtiseo@ao.pr.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Damato
authors.affiliation: Medical Oncology Unit, Azienda USL Modena, Hospital "Ramazzini", Carpi, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Longo
authors.affiliation: Department of Oncology, Haematology and Respiratory Diseases Clinic, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Barbieri
authors.affiliation: Department of Oncology, Haematology and Respiratory Diseases Clinic, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Bertolini
authors.affiliation: Operative Unit of Thoracic Surgery, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stefani
authors.affiliation: Operative Unit of Pathology, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Migaldi
authors.affiliation: Section of Anatomy and Pathology, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Gnetti
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Camisa
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bordi
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Buti
authors.affiliation: Unit of Pathologic Anatomy, Azienda USL Valle d'Aosta, Regional Hospital "Parini", Aosta, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D060890:B7-H1 Antigen / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis; D013945:Thymoma / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology*; D013953:Thymus Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D060890:B7-H1 Antigen; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases
keywords: Gene mutations; PD-L1; Thymic carcinoma; Thymoma; c-KIT