title: MAPKAP kinase 2 overexpression influences prognosis in gastrointestinal stromal tumors and associates with copy number variations on chromosome 1 and expression of p38 MAP kinase and ETV1.
abstract: OBJECTIVE
  ETV1 has been proposed to be activated by KIT mutations in gastrointestinal stromal tumors (GIST). The aim of the study was to evaluate the clinical role of ETV1 and associated proteins in GIST.
  
  
  METHODS
  Expressions of ETV1, MAPKAP kinase 2 (MAPKAPK2), phosphorylated p38 MAP kinase (pp38), phosphorylated MSK1 (pMSK1), phosphorylated RSK1, COP1, and KIT protein were determined immunohistochemically in 139 GISTs. Sequence analysis of KIT, PDGFRA, and MAPKAPK2 and FISHs of ETV1 as well as chromosomes 1 and 7 were done.
  
  
  RESULTS
  Prominent ETV1 expression was seen in 50% of GISTs, but no correlation with clinical outcome was found. Correlation of ETV1 expression and KIT mutation was seen in 60% of cases. MAPKAPK2 overexpression (n = 62/44.6%) correlated with pp38 expression (P = 0.021, χ(2) test) and alterations of chromosome 1 (n = 17, P = 0.024, χ(2) test). In one of 20 sequenced cases with high MAKAPK2 expression, a putative damaging MAPKAPK2 gene mutation was found. All relapsing GISTs with very low/low risk according to Fletcher showed high MAPKAPK2 and KIT expression. MAPKAPK2 overexpression was an independent prognostic factor for disease-free survival (P = 0.006, Cox regression).
  
  
  CONCLUSIONS
  ETV1 is not universally overexpressed in GIST and seems to also be induced by pathways other than KIT mutation. Nevertheless, its clinical relevance is low. Overexpression of ETV1 inhibitor MAPKAPK2 is associated with shorter survival in GIST, indicating a clinically relevant role of this gene not reported previously. Patients with low-risk GISTs showing MAPKAPK2 overexpression might profit from early adjuvant tyrosine kinase inhibitor therapy.
authors.affiliation: Departments of Surgery and Obstetrics and Gynecology, Clinical Institute of Pathology, Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.forename: Andrea
authors.initials: A
authors.lastname: Beer
authors.forename: Ursula
authors.initials: U
authors.lastname: Vinatzer
authors.forename: Susanne
authors.initials: S
authors.lastname: Stary
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.forename: Nadine
authors.initials: N
authors.lastname: Nirtl
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Schoppmann
mesh_terms: D000368:Aged; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C095239:ETV1 protein, human; C471981:COP1 protein, human; C069329:RPS6KA1 protein, human