title: Inactivating Mutations of RB1 and TP53 Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors.
abstract: OBJECTIVE
  Loss-of-function mutations in TP53 and CDKN2A have been found at varying frequencies in gastrointestinal stromal tumors (GISTs), while no mutations of RB1 have been reported to date. The aim of the current study was to determine the mutation frequency of TP53, RB1, and CDKN2A in GISTs.
  
  
  METHODS
  A cohort of 83 primary untreated GISTs was analyzed for mutations in TP53, RB1, and CDKN2A by massive parallel sequencing. Tumors with mutations in TP53 and RB1 were analyzed by fluorescence in situ hybridization for the corresponding gene loci.
  
  
  RESULTS
  Two GISTs harbored inactivating mutations in RB1, and two other GISTs displayed inactivating mutations in TP53 All four tumors were KIT mutant high-risk tumors with highly cellular sarcomatous histomorphology and variable combinations of plump spindle cells to epithelioid highly atypical cells and high mitotic activity. Three of these patients developed recurrent or metastatic disease, while the fourth patient showed tumor rupture intraoperatively. The combined overall frequency of TP53 and RB1 mutations was 13% considering high-risk or malignant GISTs.
  
  
  CONCLUSIONS
  TP53 and RB1 mutations seem to be restricted to high-risk/malignant GISTs and occur at an equal although relatively low frequency.
authors.affiliation: From the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Merten
authors.affiliation: From the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: From the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Moskalev
authors.affiliation: From the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Giedl
authors.affiliation: Institute of Pathology, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kayser
authors.affiliation: Institute of Pathology, St. Vincentius Hospital, Karlsruhe, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Geddert
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.
authors.forename: Inga-Marie
authors.initials: IM
authors.lastname: Schaefer
authors.affiliation: Clinic for Gastroenterology and Gastrointestinal Oncology.
authors.forename: Silke
authors.initials: S
authors.lastname: Cameron
authors.affiliation: Institute of Pathology, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.affiliation: Institute of Pathology, Georg August University, Göttingen, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: From the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: From the Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany florian.haller@uk-erlangen.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases
keywords: CDKN2A; GIST; Mutation; RB1; TP53