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ATRX in Diffuse Gliomas With its Mosaic/Heterogeneous Expression in a Subset
Suvendu Purkait1, Christopher A Miller2, Anupam Kumar1
1Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Brain Pathology (Zurich, Switzerland)
|February 3, 2016
Summary
ATRX expression loss is common in lower-grade gliomas and secondary glioblastomas, linked to IDH1/TP53 mutations. Mosaic ATRX staining in glioblastomas warrants further mutation analysis.
Area of Science:
- Neuro-oncology
- Molecular Pathology
- Cancer Genetics
Background:
- Alpha-thalassemia X-linked intellectual disability (ATRX) protein is crucial in maintaining chromatin structure.
- Alterations in ATRX expression are implicated in various cancers, including gliomas.
- Understanding ATRX expression patterns and their genetic correlations is vital for glioma classification and prognosis.
Purpose of the Study:
- To evaluate ATRX immunohistochemistry expression in diverse glioma grades and subtypes.
- To correlate ATRX expression patterns with hallmark genetic alterations like IDH1, TP53 mutations, and 1p/19q codeletion.
- To characterize mosaic/heterogeneous ATRX staining patterns in gliomas and investigate their association with mutation status.
Main Methods:
- Immunohistochemistry for ATRX was performed on 176 glioma cases.
- Glioma cases were classified based on ATRX staining patterns: positive, negative, or mosaic/heterogeneous.
- Next-generation sequencing was conducted on five cases exhibiting heterogeneous ATRX staining.
Main Results:
- ATRX immune-negativity was frequent in grade II/III astrocytic, oligoastrocytic tumors, and secondary glioblastomas (GBMs), but rare in primary GBMs and oligodendrogliomas.
- Loss of ATRX expression strongly correlated with IDH1 and/or TP53 mutations and was mutually exclusive with 1p/19q codeletion.
- Mosaic/heterogeneous ATRX staining, observed exclusively in GBMs (21.2%), included admixtures of positive/negative nuclei or separate positive/negative fragments. ATRX or DAXX mutations were found in 40% of mosaic cases.
Conclusions:
- ATRX expression patterns, particularly immune-negativity and mosaic staining, are significant in glioma subtyping and correlate with specific genetic alterations.
- Mosaic ATRX staining in GBMs is associated with underlying ATRX or DAXX mutations and suggests potential intra-tumoral heterogeneity.
- Glioma cases with heterogeneous ATRX staining, especially those with distinct negative fragments, should be considered for further molecular mutation analysis.
