title: ATRX loss in adult supratentorial diffuse astrocytomas correlates with p53 over expression and IDH1 mutation and predicts better outcome in p53 accumulated patients.
abstract: BACKGROUND
  IDH1/2 mutation, 1p/19q-codeletion and MGMT hypermethylation are well known molecular markers for gliomas. ATRX and p53 alterations are two lineage-specific genetic aberrations in diffuse astrocytic tumors. The aim of the present study is to clarify the significance of ATRX loss and its correlation with p53 overexpression, IDH1/2 mutations, 1p/19q-codeletion and MGMT hypermethylation in supertentorial astrocytoma, and to determine the prognostic value of these factors in Chinese patients.
  
  
  RESULTS
  A total of 135 adult supertentorial astrocytomas were evaluated. ATRX loss was detected by immunohistochemistry (IHC) and was shown to be much less frequent in pGBs (3.5%) than in grade II, III astrocytomas and IV sGBs (31%). Direct sequencing and/or IHC analysis of the IDH1R132H gene mutation and p53 accumulation demonstrated correlation with age. Strong correlations were found between ATRX loss and IDH1R132H mutation, p53 overexpression as well as MGMT hypermethylation. 1p/19q-codeletion detected by fluorescence in situ hybridization (FISH) showed mutually exclusive with ATRX loss and p53 accumulation. In addition, patients with p53 overexpression combined with ATRX alterations demonstrated substantially longer survival than patients with wild-type ATRX.
  
  
  CONCLUSIONS
  There may be interactions among these distinct molecules in astrocytoma development. ATRX loss may predict better clinical outcome in astrocytoma patients with p53 overexpression as compared to patients with wild-type ATRX. Tumors with astrocytoma phenotype accompanied by 1p/19q-codeletion and IDH1R132H mutation are mutually exclusive with ATRX and p53 alterations. Routine IHC can be used for evaluation of ATRX loss, p53 protein accumulation and IDH1R132H mutation, which may allow a means of classification of astrocytoma outcome.
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Shao
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Pathology, Beijing Sanbo Brain Hospital, Beijing, China.
authors.forename: Xue-Ling
authors.initials: XL
authors.lastname: Qi
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Ma
authors.affiliation: Department of Epidemiology and Health Statistics, Peking University, Beijing, China.
authors.forename: Wei-Ning
authors.initials: WN
authors.lastname: Yi
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China and Department of Neuropathology, Harborview Medical Center, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Zhong
authors.affiliation: Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing. China qingchang@bjmu.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D001254:Astrocytoma / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics*; D015173:Supratentorial Neoplasms / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000075924:X-linked Nuclear Protein; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein; D045643:DNA Repair Enzymes