ATRX immunostaining predicts IDH and H3F3A status in gliomas.

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

doi:10.1186/s40478-016-0331-6

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0331-6) contains supplementary material, which is available to authorized users.

Highlights

Gliomas, including astrocytoma and oligodendroglioma are the most frequent primary intraaxial neoplasms
Loss of nuclear as α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX) expression is accompanied with an astrocytic tumor lineage and a younger age of onset Loss of nuclear ATRX in tumor cells was found in 210 out of 885 (24 %) of the tumors (Mean positive nuclei: 7.9 %, 95 % confidence intervals (CIs): 5.6–10.1)
ATRX loss is significantly associated with tumors of astrocytic lineage including astrocytoma grade II (Fig. 1c), III (Fig. 1d) and glioblastoma grade IV with the exception of pilocytic astrocytomas (p < 0.001)

Summary

Introduction

Gliomas, including astrocytoma and oligodendroglioma are the most frequent primary intraaxial neoplasms. Diffuse astrocytomas are characterized by invasive growth and may progress to glioblastomas through acquisition of additional mutations [1]. Many of these tumors have tumor-promoting mutations in the isocitrate dehydrogenase (IDH) 1 and/or 2 genes [2, 3]. ATRX alterations are frequent and, according to the current knowledge, are associated with astrocytic tumors carrying additional IDH1/2 and TP53 mutations [9, 10]. Missense and truncating mutations of ATRX gene lead to loss of expression in gliomas [8, 9] and correlates with better clinical outcome in a subset of IDH1 mutant tumors [11]

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