title: Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries.
abstract: BACKGROUND
  Kinases represent potential therapeutic targets in pancreatic endocrine tumours (PETs).
  
  
  METHODS
  Thirty-five kinase genes were sequenced in 36 primary PETs and three PET cell lines: (i) 4 receptor tyrosine kinases (RTK), epithelial growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tyrosine-protein kinase KIT (KIT), platelet-derived growth factor receptor alpha (PDGFRalpha); (ii) 6 belonging to the Akt/mTOR pathway; and (iii) 25 frequently mutated in cancers. The immunohistochemical expression of the four RTKs and the copy number of EGFR and HER2 were assessed in 140 PETs.
  
  
  RESULTS
  Somatic mutations were found in KIT in one and ATM in two primary neoplasms. Among 140 PETs, EGFR was immunopositive in 18 (13%), HER2 in 3 (2%), KIT in 16 (11%), and PDGFRalpha in 135 (96%). HER2 amplification was found in 2/130 (1.5%) PETs. KIT membrane immunostaining was significantly associated with tumour aggressiveness and shorter patient survival. PET cell lines QGP1, CM and BON harboured mutations in FGFR3, FLT1/VEGFR1 and PIK3CA, respectively.
  
  
  CONCLUSIONS
  Only rare PET cases, harbouring either HER2 amplification or KIT mutation, might benefit from targeted drugs. KIT membrane expression deserves further attention as a prognostic marker. ATM mutation is involved in a proportion of PET. The finding of specific mutations in PET cell lines renders these models useful for preclinical studies involving pathway-specific therapies.
authors: ARC-NET Center for the Applied Research on Cancer-Networking.
authors: V
authors: V
authors: Corbo
authors: ARC-NET Center for the Applied Research on Cancer-Networking.
authors: S
authors: S
authors: Beghelli
authors: Department of Pathology and Diagnostics.
authors: S
authors: S
authors: Bersani
authors: Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, Italy.
authors: D
authors: D
authors: Antonello
authors: Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, Italy.
authors: G
authors: G
authors: Talamini
authors: Department of Pathology and Diagnostics.
authors: M
authors: M
authors: Brunelli
authors: Department of Pathology and Diagnostics.
authors: P
authors: P
authors: Capelli
authors: Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, Italy.
authors: M
authors: M
authors: Falconi
authors: ARC-NET Center for the Applied Research on Cancer-Networking; Department of Pathology and Diagnostics. Electronic address: aldo.scarpa@univr.it.
authors: A
authors: A
authors: Scarpa
mesh_terms: D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004701:Endocrine Gland Neoplasms / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D011494:Protein Kinases