title: High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event.
abstract: OBJECTIVE
  (1) To test whether in genomewide expression profiling differentially expressed genes were also distinct on the protein level including KIT and PDGFRA (2) to correlate the expression with clinicopathological parameters (3) to identify activating mutations that might be eligible for tyrosine kinase inhibitor therapy by mutational analysis of tumors with high expression.
  
  
  METHODS
  Gastroenteropancreatic neuroendocrine tumors (GEP NETs) from 119 patients were analyzed for protein expression of ten biomarkers. Mutational analysis of KIT (exon 9, 13, 11 and 17) and PDGFRA (exons 12 and 18) was performed on those samples that showed high protein expression.
  
  
  RESULTS
  High KIT expression was observed in 13% of all specimens, PDGFRA in 33%, CK19 in 26%, CK7 in 2%, CK20 in 5%, S100 in 6%, CD56 in 25%, Chromogranin in 55%, and Synapthophysin in 80%. High expression of KIT and PDGFRA was significantly correlated with shorter disease-specific survival (P = 0.003, P = 0.018, respectively). In multivariate analysis expression of PDGFRA, radicality of surgical treatment and WHO grading influenced disease-specific 10-year survival independently (P = 0.032, P = 0.001 and P = 0.008, respectively). Mutational analysis of highly expressed specimens (n = 51) reveals a novel mutation of KIT in exon 11 (K558N_V559insP) in a well-differentiated metastatic pancreatic neuroendocrine tumor.
  
  
  CONCLUSIONS
  High expression of KIT and PDGFRA was significantly correlated with shorter patients survival and could serve as prognostic marker. Mutations of the KIT gene might open new avenues for tyrosine kinase inhibitor therapy in a subset of patients with advanced pancreatic neuroendocrine tumors.
authors.affiliation: Institute of Pathology, Friedrich-Schiller University, Jena University Hospital, Ziegelmühlenweg 1, 07743 Jena, Germany. thomas.knoesel@med.uni-jena.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Annelore
authors.initials: A
authors.lastname: Altendorf-Hofmann
authors.forename: Christine
authors.initials: C
authors.lastname: Danielczok
authors.forename: Martin
authors.initials: M
authors.lastname: Freesmeyer
authors.forename: Utz
authors.initials: U
authors.lastname: Settmacher
authors.forename: Christine
authors.initials: C
authors.lastname: Wurst
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.forename: Lin Lin
authors.initials: LL
authors.lastname: Yang
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D019002:CD56 Antigen / Q000378:metabolism; D053379:Chromogranin A / Q000378:metabolism; D004252:DNA Mutational Analysis; D004067:Digestive System Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000401:mortality; D053208:Kaplan-Meier Estimate; D007633:Keratins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D016017:Odds Ratio; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000401:mortality; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000401:mortality; D016708:Synaptophysin / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D019002:CD56 Antigen; D053379:Chromogranin A; D019394:Ki-67 Antigen; C522918:NCAM1 protein, human; D009418:S100 Proteins; D016708:Synaptophysin; D007633:Keratins; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha