Common Molecular Marker for Glioma: ATRX

ATRX is a chromatin remodeling protein belonging to the SWI/SNF family of chromatin remodeling proteins. ATRX protein undergoes cell cycle-dependent phosphorylation, regulating its binding to the nuclear matrix and chromatin, indicating its involvement in interphase gene regulation and chromosome segregation during mitosis. Therefore, ATRX is crucial for maintaining genomic stability. Mutations in this gene are associated with X-linked mental retardation (XLMR) syndrome, often accompanied by alpha-thalassemia mental retardation syndrome (X-linked alpha thalassemia mental retardation syndrome), abbreviated as ATRX syndrome. ATRX gene mutations have been found in various malignant tumors, including gliomas, pancreatic neuroendocrine tumors, and osteosarcomas, with more applications in gliomas.

In 2011, Heaphy et al. discovered ATRX gene mutations in central nervous system tumors. Subsequent studies confirmed that ATRX gene mutations mainly occur in diffuse astrocytomas. In the 2014 consensus of the International Society of Neuropathology, ATRX gene mutation/loss was identified as a characteristic molecular marker for diffuse astrocytomas. The 2016 WHO revision of central nervous system tumors proposed that most diffuse and anaplastic astrocytomas with IDH mutations often have concurrent ATRX and P53 gene mutations. China’s 2018 edition of glioma diagnosis and treatment guidelines listed ATRX immunohistochemistry as helpful for the diagnostic classification of IDH-mutant gliomas.

• In gliomas, the proportion of IDH-mutant diffuse gliomas with ATRX loss is as high as over 90%. 55%-85% of grade II and III astrocytomas exhibit ATRX loss, while ATRX loss is rare in primary glioblastomas and oligodendrogliomas. ATRX can serve as a specific molecular marker for astrocytomas (IDH-mutant type).

• In grade II/III gliomas, ATRX loss is often accompanied by IDH1/2 mutations. ATRX loss is significantly correlated with TP53 mutation and/or p53 overexpression and is mutually exclusive with 1p/19q co-deletion. Therefore, ATRX can be used as an auxiliary tool for IDH mutation status, 1p/19q co-deletion, and histological diagnosis to differentiate and clarify tumor types.

• The prognosis of astrocytic tumor patients with ATRX loss is significantly better than that of IDH-mutant astrocytic tumor patients expressing ATRX (Figure 1).

Figure 1 ATRX Expression Level and Survival Analysis

ATRX protein expression in adult gliomas is either lost or retained in an opposing manner, with few “indeterminate” categories. ATRX protein expression is completely correlated with ATRX gene mutations and is significantly associated with histological subtypes and alterations in other key biomolecules known to occur in diffuse gliomas (IDH and TP53 mutations and 1p/19q co-deletion). Therefore, immunohistochemical analysis of ATRX protein expression can serve as a surrogate method for assessing ATRX gene mutations, with a high concordance rate.

References:

[1] Ikemura M , Shibahara J , Mukasa A , et al. Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas. Histopathology[J]. 2016, 69(2):260-267

[2] 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[J]. 2013 Sep;126(3):443-451. doi: 10.1007/s00401-013-1156-z.

[3] Overview of the 2016 WHO Classification of Tumours of the Central Nervous System, 4th Edition Revised, and Introduction to the Glioma Section. Chinese Journal of Pathology[J], 2016, 045(011):745-747.

[4] Piao Yueshan, Zhang Liyan, et al. Application of ATRX in Glioma Diagnosis and Patient Prognosis Assessment [J]. Chinese Journal of Pathology, 2017, 46(10):690-694.

[5] Ebrahimi A , Skardelly M , Bonzheim I , et al. ATRX immunostaining predicts IDH and H3F3A status in gliomas[J]. Acta Neuropathologica Communications, 2016, 4(1):1-10.