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

• DOI: 10.18632/oncotarget.689
• Publication Date: 2015-09-16T21:48:50Z
• Authors: Kasthuri Kannan; Akiko Inagaki; Joachim Silber; Daniel Gorovets; Jianan Zhang; Edward R. Kastenh...; Adriana Heguy; John H. Petrini; Timothy A. Chan; Jason T. Huse
• Keywords: ATRX

// Kasthuri Kannan 1,4 , Akiko Inagaki 2 Joachim Silber Daniel Gorovets Jianan Zhang Edward R. Kastenhuber Adriana Heguy 4 John H. Petrini Timothy A. Chan 3,4 and Jason T. Huse 1 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Molecular Biology, 3 Radiation Oncology, Human Oncology Pathogenesis Program, Correspondence: Huse, email: Keywords : glioma, astrocytoma, IDH, ATRX, whole-exome sequencing Received October 01, 2012, Accepted 09, Published 11, 2012 Abstract The molecular foundations lower-grade gliomas (LGGs)—astrocytoma, oligodendroglioma, oligoastrocytoma—remain less well characterized than those their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase (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 mutation drive oncogenesis LGG. We performed whole exome LGGs, followed by focused resequencing an 28, found a high incidence the ATRX gene (α thalassemia/mental retardation syndrome X-linked). forms core component chromatin remodeling complex active telomere biology. identified multiple tumor types cause alternative lengthening telomeres (ALT), presumed precursor instability. In our samples, was entirely restricted IDH-mutant tumors, closely correlated TP53 astrocytic differentiation, mutually exclusive 1p/19q codeletion, hallmark oligodendroglioma. Moreover, highly enriched tumors so-called early progenitor-like transcriptional subclass (~85%), which prior work has linked specific cells origin forebrain subventricular zone. Finally, ALT, providing mechanistic link summary, findings both identify as defining determinant for large subset direct implications on across wide spectrum LGGs.