gms | German Medical Science

Introduction: Recent studies on diffuse gliomas have shown frequent alterations in the α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX).

Objectives: Validation of an interobserver-reliant cutoff to determine nuclear ATRX loss is necessary. The reliability of ATRX in predicting both, isocitrate dehydrogenase (IDH) and H3 histone, family 3A (H3F3A) mutations in gliomas, is not fully elucidated.

Patients & Methods: We analysed ATRX expression status by immunohistochemistry in a large series of 1064 gliomas and correlated the results to IDH, H3F3A and loss of heterozygosity (LOH) 1p/19q status in these tumors. In addition, the predictive potential of ATRX in the group of diffuse gliomas was investigated.

Results: Tumors with ATRX loss exhibited in average 7.9% ATRX positive nuclei. (95% CI: 5.6-10.1) establishing a 10% cutoff for discrimination from tumors with ATRX retention (mean: 67.1%; 95% CI: 64.4-69.8). Scoring and classification of two independent neuropathologists was highly concordant (Pearsons Chi-square: p<0.0001; Cohens kappa agreement: 0.18).

Loss of nuclear ATRX expression (24%) was accompanied with an astrocytic tumor lineage, a younger age of onset, IDH1/2 and H3F3A mutation (p<0.0001). Of 193 glial tumors with nuclear ATRX loss, 171 (89%) had an IDH1 or IDH2 mutation. Among the remaining 22 cases (11%) with ATRX loss and IDH wild type status, 6 cases had a H3F3A G34R mutation (3%) and 3 cases had a H3F3A K27M mutation (2%). ATRX retention in IDH1/2 mutant tumors was strongly associated with LOH 1p/19q and oligodendroglioma histology (p<0.0001).

Grade II-IV 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).

Conclusion: ATRX is a potential marker for prediction of IDH/H3F3A mutations and substratification of diffuse gliomas into survival relevant tumor groups.