Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2016

Open Access 01-12-2016 | Research

ATRX immunostaining predicts IDH and H3F3A status in gliomas

Authors: Azadeh Ebrahimi, Marco Skardelly, Irina Bonzheim, Ines Ott, Helmut Mühleisen, Franziska Eckert, Ghazaleh Tabatabai, Jens Schittenhelm

Published in: Acta Neuropathologica Communications | Issue 1/2016

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
2.
Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118:469–74.CrossRefPubMed
3.
Watanabe T, Nobusawa S, Kleihues P, et al. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174:1149–53.CrossRefPubMedPubMedCentral
4.
Schittenhelm J, Mittelbronn M, Meyermann R, et al. Confirmation of R132H mutation of isocitrate dehydrogenase 1 as an independent prognostic factor in anaplastic astrocytoma. Acta Neuropathol. 2011;122:651–2.CrossRefPubMed
5.
Sottoriva A, Spiteri I, Piccirillo SG, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A. 2013;110:4009–14.CrossRefPubMedPubMedCentral
6.
Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.CrossRefPubMed
7.
Bourne TD, Schiff D. Update on molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol. 2010;6:695–701.CrossRefPubMed
8.
Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226–31.CrossRefPubMed
9.
Liu XY, Gerges N, Korshunov A, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol. 2012;124:615–25.CrossRefPubMed
10.
Kannan K, Inagaki A, Silber J, et al. Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget. 2012;3:1194–203.CrossRefPubMedPubMedCentral
11.
Wiestler B, Capper D, Holland-Letz T, et al. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol. 2013;126:443–51.CrossRefPubMed
12.
International Agency for Research on Cancer. Pathology & Genetics: WHO classification of Tumours of the Central Nervous System. Lyon: IARC Press; 2007.
13.
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.CrossRefPubMed
14.
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–203.CrossRefPubMedPubMedCentral
15.
Okita Y, Narita Y, Miyakita Y, et al. IDH1/2 mutation is a prognostic marker for survival and predicts response to chemotherapy for grade II gliomas concomitantly treated with radiation therapy. Int J Oncol. 2012;41:1325–36.PubMed
16.
Thon N, Eigenbrod S, Grasbon-Frodl EM, et al. Novel molecular stereotactic biopsy procedures reveal intratumoral homogeneity of loss of heterozygosity of 1p/19q and TP53 mutations in World Health Organization grade II gliomas. J Neuropathol Exp Neurol. 2009;68:1219–28.CrossRefPubMed
17.
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.CrossRefPubMed
18.
Cohen J. Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychol Bull. 1968;70:213–20.CrossRefPubMed
19.
Therkildsen C, Ladelund S, Rambech E, et al. Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome. Eur J Neurol. 2015;22:717–24.CrossRefPubMed
20.
van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344–50.CrossRefPubMed
21.
Hartmann C, Hentschel B, Wick W, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010;120:707–18.CrossRefPubMed
22.
Reuss DE, Mamatjan Y, Schrimpf D, et al. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol. 2015;129:867–73.CrossRefPubMedPubMedCentral
23.
Jiao Y, Killela PJ, Reitman ZJ, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 2012;3:709–22.CrossRefPubMedPubMedCentral
24.
25.
26.
Nguyen DN, Heaphy CM, de Wilde RF, et al. Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol. 2013;23:237–43.CrossRefPubMed
27.
Reuss DE, Sahm F, Schrimpf D, et al. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol. 2015;129:133–46.CrossRefPubMed
28.
29.
Cai J, Yang P, Zhang C, et al. ATRX mRNA expression combined with IDH1/2 mutational status and Ki-67 expression refines the molecular classification of astrocytic tumors: evidence from the whole transcriptome sequencing of 169 samples samples. Oncotarget. 2014;5:2551–61.CrossRefPubMedPubMedCentral
30.
Wiestler B, Capper D, Sill M, et al. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol. 2014;128:561–71.CrossRefPubMed
31.
Pathak P, Jha P, Purkait S, et al. Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM. J Neurooncol. 2015;121:489–97.CrossRefPubMed
32.
Skardelly M, Brendle E, Noell S, et al. Predictors of preoperative and early postoperative seizures in patients with intra-axial primary and metastatic brain tumors: A retrospective observational single center study. Ann Neurol. 2015;78:917–28.CrossRefPubMed
33.
Dubbink HJ, Atmodimedjo PN, Kros JM, et al. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial. Neuro Oncol. 2015;18(3):388–400. doi:10.​1093/​neuonc/​nov182.CrossRefPubMed
34.
Leeper HE, Caron AA, Decker PA, et al. IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget. 2015;6:30295–305.PubMedPubMedCentral
35.
Hewer E, Vajtai I, Dettmer MS, et al. Combined ATRX/IDH1 immunohistochemistry predicts genotype of oligoastrocytomas. Histopathology. 2016;68:272–8.CrossRefPubMed
36.
Sahm F, Reuss D, Koelsche C, et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 2014;128:551–9.CrossRefPubMed
37.
Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 2015;372:2481–98.CrossRef
38.
Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015;372:2499–508.CrossRefPubMedPubMedCentral
Metadata
Title
ATRX immunostaining predicts IDH and H3F3A status in gliomas
Authors
Azadeh Ebrahimi
Marco Skardelly
Irina Bonzheim
Ines Ott
Helmut Mühleisen
Franziska Eckert
Ghazaleh Tabatabai
Jens Schittenhelm
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2016
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-016-0331-6

Other articles of this Issue 1/2016

Acta Neuropathologica Communications 1/2016 Go to the issue

Erratum

Erratum to: Multiplex immunoassay characterization and species comparison of inflammation in acute and non-acute ischemic infarcts in human and mouse brain tissue

Research

Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX-

Research

The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer’s disease

Research

Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD

Research

Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection

Research

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma