Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma

Abstract

The molecular foundations of lower-grade gliomas (LGGs)—astrocytoma, oligodendroglioma, and oligoastrocytoma—remain less well characterized than those of their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events. However, while IDH mutations appear to dramatically alter cellular epigenomic landscapes, definitive downstream transformative mechanisms have not been characterized. It remains likely, therefore, that additional genomic abnormalities collaborate with IDH mutation to drive oncogenesis in LGG. We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, and found a high incidence of mutations in the ATRX gene (α thalassemia/mental retardation syndrome X-linked). ATRX forms a core component of a chromatin remodeling complex active in telomere biology. Mutations in ATRX have been identified in multiple tumor types and appear to cause alternative lengthening of telomeres (ALT), a presumed precursor to genomic instability. In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma. Moreover, ATRX mutation was highly enriched in tumors of so-called early progenitor-like transcriptional subclass (~85%), which our prior work has linked to specific cells of origin in the forebrain subventricular zone. Finally, ATRX mutation correlated with ALT, providing a mechanistic link to genomic instability. In summary, our findings both identify ATRX mutation as a defining molecular determinant for a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs.

Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

“…Thus, in several clinical studies, mutations in ATRX were found to be tightly associated with the ALT pathway in various types of tumors (10,11,(20)(21)(22)(23). This correlation has also been observed in cultured cells (24,25).…”

The Evolving Role of Molecular Markers in the Diagnosis and Management of Diffuse Glioma

“…Recent work has shown that mutations in the SWI/SNF chromatin regulator ATRX frequently occur in gliomas, and are almost invariably associated with mutations of TP53 and IDH1 genes across glioma entities (58,64,65). A strong correlation between inactivation of ATRX and the phenomenon known as alternative lengthening of telomeres has been postulated (64).…”

Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span

“…The biological impact of ATRX mutations in humans appears to vary according to the extent and timing of disruption. In humans, ATRX somatic frameshift and nonsense mutations that completely abolish protein function have been identified in pancreatic neuroendocrine tumors (PanNETs) (5-7), pediatric and adult glioblastomas, and other cancers of the CNS (8)(9)(10)(11)(12), underscoring the anti-tumorigenic roles of ATRX. Tumors with ATRX mutations often harbor long telomeres, which are characteristic of the telomere maintenance mechanism known as alternative lengthening of telomeres (ALT) (6,7,11,13,14).…”

“…In humans, ATRX somatic frameshift and nonsense mutations that completely abolish protein function have been identified in pancreatic neuroendocrine tumors (PanNETs) (5-7), pediatric and adult glioblastomas, and other cancers of the CNS (8)(9)(10)(11)(12), underscoring the anti-tumorigenic roles of ATRX. Tumors with ATRX mutations often harbor long telomeres, which are characteristic of the telomere maintenance mechanism known as alternative lengthening of telomeres (ALT) (6,7,11,13,14). Conversely, hypomorphic inherited mutations of the ATRX gene cause a rare developmental disorder, ATR-X syndrome (OMIM 301040), with diagnostic features of severe cognitive deficits, microcephaly, seizures, short stature, developmental delay, and α-thalassemia, without increased neoplasia incidence (15)(16)(17).…”