Laboratory Medicine Pulse

Genome-wide molecular approaches have substantially elucidated molecular alterations and pathways involved in the oncogenesis of brain tumors. In gliomas, several molecular biomarkers including IDH mutation, 1p/19q co-deletion, and MGMT promotor methylation status have been introduced into neuropathological practice. Recently, mutations in the ATRX (α-thalassemia/mental retardation syndrome X-linked) gene have been detected in gliomas of various subtypes and grades. In independent studies, a prognostic impact of ATRX mutations in the context of other molecular markers could be demonstrated, thus turning ATRX into a new candidate biomarker for routine clinical practice. ATRX The ATRX gene is located on chromosome Xq21.1 and encodes a protein that belongs to the H3.3-ATRX-DAXX chromatinremodeling pathway. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and α-thalassemia. ATRX is required for the incorporation of the histone variant H3.3 at pericentric heterochromatin and at telomeres, as well as at several transcription factor binding sites. Perturbation of ATRX has been associated with a wide range of effects: altered patterns of DNA methylation (at subtelomeres, heterochromatic repeats, and ribosomal DNA), aberrant chromosome congression in mitosis, and segregation in meiosis, as well as telomere dysfunction. ATRX expression in gliomas Loss of nuclear ATRX seems to be a good surrogate marker for ATRX mutations and ATRX expression can – similarly to mutant IDH1 protein – be easily assessed in the routine neuropathological setting with a commercially available antibody (HPA001906, Sigma-Aldrich, St. Louis, MO, USA). Physiologically, ATRX protein is ubiquitously expressed in cell nuclei. Mutations in the ATRX gene result in a loss of nuclear protein expression in tumor cells, but retained expression in non-tumor cells (e.g., endothelial cells, pre-existing glial cells), which serve as a positive internal control, analogously to Editor in chief