ATRX immunostaining predicts IDH and H3F3A status in gliomas.
Gliomas are the most frequent intraaxial CNS neoplasms with a heterogeneous molecular background. Recent studies on diffuse gliomas have shown frequent alterations in the genes involved in chromatin remodelling pathways such as α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX). Yet, the reliability of ATRX in predicting isocitrate dehydrogenase (IDH) and H3 histone, family 3A (H3F3A) mutations in gliomas, is unclear.We analysed the ATRX expression status by immunohistochemistry, in a large series of 1064 gliomas and analysed the results in correlation to IDH, H3F3A and loss of heterozygosity (LOH) 1p/19q status in these tumors. We also investigated the prognostic potential of ATRX concerning the clinical outcome of patients with diffuse gliomas.According to our results, loss of nuclear ATRX expression was accompanied with an astrocytic tumor lineage and a younger age of onset. ATRX loss in astrocytomas was also strongly associated with IDH1/2 and H3F3A mutation (p < 0.0001). Among 196 glial tumors with nuclear ATRX loss, 173 (89 %) had an IDH1 or IDH2 mutation. Among the remaining 23 cases (11 %) with ATRX loss and IDH wild type status, 7 cases had a H3F3A G34R mutation (3 %) and 2 cases had a H3F3A K27M mutation (1 %). ATRX retention in IDH1/2 mutant tumors was strongly associated with LOH 1p/19q and oligodendroglioma histology (p < 0.0001). We also confirmed the significant prognostic role of ATRX. Diffuse gliomas with ATRX loss (n = 137, median 1413 days, 95 % CI: 1065-1860 days) revealed a significantly better clinical outcome compared with tumors with ATRX retention (n = 335, median: 609, 95 % CI: 539-760 days, HR = 1.81, p < 0.0001).In conclusion, ATRX is a potential marker for prediction of IDH/H3F3A mutations and substratification of diffuse gliomas into survival relevant tumor groups. Such classification is of great importance for further clinical decision making especially concerning the therapeutic options available for diffuse gliomas.
Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Calwerstr. 3, D-72076, Tuebingen, Germany.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Azadeh
A
Ebrahimi
Department of Neurosurgery, University Hospital of Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, 72076, Germany.|Interdisciplinary Division of Neurooncology, Departments of Vascular Neurology, Neurosurgery University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, 72076, Germany.|Laboratory for Clinical and Experimental Neurooncology, Hertie-Institute for Clinical Brain Research, Tuebingen, Germany.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Marco
M
Skardelly
Department of Pathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, 72076, Germany.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Irina
I
Bonzheim
Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Calwerstr. 3, D-72076, Tuebingen, Germany.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Ines
I
Ott
Department of Pathology, Institute of Pathology and Neuropathology, Ludwigsburg Hospital, Ludwigsburg, 71640, Germany.
Helmut
H
Mühleisen
Department of Radiation Oncology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, 72076, Germany.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Franziska
F
Eckert
Interdisciplinary Division of Neurooncology, Departments of Vascular Neurology, Neurosurgery University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, 72076, Germany.|Laboratory for Clinical and Experimental Neurooncology, Hertie-Institute for Clinical Brain Research, Tuebingen, Germany.|Center for Personalized Medicine, Eberhard Karls University of Tuebingen, Tuebingen, Germany.|German Consortium for Translational Cancer Research (DKTK), DKFZ partner site, Tuebingen, Germany.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Ghazaleh
G
Tabatabai
Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Calwerstr. 3, D-72076, Tuebingen, Germany. jens.schittenhelm@med.uni-tuebingen.de.|Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany. jens.schittenhelm@med.uni-tuebingen.de.
Jens
J
Schittenhelm
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006657:Histones / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D000075924:X-linked Nuclear Protein; D055815:Young Adult
D014408:Biomarkers, Tumor; C000609950:H3-3A protein, human; D006657:Histones; D009687:Nuclear Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
ATRX; Astrocytoma; Glioma; H3F3A; IDH; Oligodendroglioma