title: P16 overexpression in BRAF-mutated gastrointestinal stromal tumors.
abstract: The aims of this study were to analyze the histopathology, immunophenotype, molecular features, and prognosis in cases of BRAF-mutated gastrointestinal stromal tumors (GISTs) and to examine the p16 expression in these tumors, and further discuss its effects on tumor formation and progression.
  
  
  
  In all, 283 GIST cases (201 KIT mutants, 12 PDGFRA mutants and 70 wild-type) from the 2010 to 2014 surgical pathology files of the Department of Pathology at Nanjing Jinling Hospital were analyzed for mutations in BRAF exon 15. Patient follow-up and clinical data were collected if available in the medical records. To determine the clinicopathological features and potential molecular mechanism, the authors examined 10 BRAF-mutated GIST cases for KIT, DOG1, SMA, desmin, S-100, Ki-67 and p16 expression.
  
  
  
  The authors identified 10 cases (3.5%) of BRAF (V600E) mutations in a series of 283 primary GISTs, without KIT (exons 9, 11, 13, 17) or PDGFRA (exons 12, 18) gene mutations. All 10 cases exhibited spindle-cell features, and the morphology and immunophenotype of these cases were no different from those in cases of KIT-mutated GISTs. The clinical results indicated that BRAF-mutated GISTs tended to occur more frequently in females (7/10), older individuals (mean age, 54.9 years) and the stomach (7/10), and that these tumors were low risk and exhibited low recurrence and mortality rates. Two different forms of p16 were identified, which presented with simultaneously strong and diffuse nuclear and cytoplasmic expression patterns.
  
  
  
  GISTs with the BRAF V600E mutation are relatively benign tumors with a distinctive molecular mechanism. The expression of the nuclear and cytoplasmic forms of p16 represent two independent mechanisms, and both seemed to control proliferation in response to oncogenic stimuli, protecting the cell from malignant transformation in BRAF-mutated GISTs.
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Shi
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Qiu-Yuan
authors.initials: QY
authors.lastname: Xia
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Rao
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Shen
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Ye
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Qun-Li
authors.initials: QL
authors.lastname: Shi
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Lu
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Heng-Hui
authors.initials: HH
authors.lastname: Ma
authors.affiliation: a Department of Pathology , Jinling Hospital, Clinical Medical School of Southern Medical University , Nanjing , P. R. China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Zhou
mesh_terms: D019943:Amino Acid Substitution; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF mutation; GIST; immunohistochemistry; p16; wild-type