ATRX loss in adult supratentorial diffuse astrocytomas correlates with p53 over expression and IDH1 mutation and predicts better outcome in p53 accumulated patients
Li-Wei Shao1,*, Yi Pan1,*, Xue-Ling Qi2,*, Yong-Xiao Li1, Xiao-Long Ma1, Wei-Ning Yi3, Jing Zhang1,4, Yan-Feng Zhong1 and Qing Chang1
1Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University, Beijing, China, 2Department of Pathology, Beijing Sanbo Brain Hospital, Beijing, China, 3Department of Epidemiology and Health Statistics, Peking University, Beijing, China and 4Department of Neuropathology, Harborview Medical Center, University of Washington School of Medicine, Seattle, WA, USA
*These authors contributed equally to this work
Offprint requests to: Chang Q. and Zhong Y.F. Department of Pathology, School of Basic Medical Science, The Third Hospital of Peking University, Peking University Health Science Center, Xue Yuan Road 38#, Beijing, 100191, China. e-mail: qingchang@bjmu.edu.cn
Summary. 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. Methods and 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 accom-panied 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. Histol Histopathol 31, 103-114 (2016)
Key words: ATRX, p53, IDH1, MGMT, Immunohisto-chemistry, Fluorescence in situ hybridization
DOI: 10.14670/HH-11-664