Global DNA methylation profiling reveals chromosomal instability in IDH-mutant astrocytomas

Yan Liu, Adwait Amod Sathe, Kalil G. Abdullah, Samuel K. McBrayer, Steven H. Adams, Andrew J. Brenner, Kimmo J. Hatanpaa, Mariano S. Viapiano, Chao Xing, Jamie M. Walker, Timothy E. Richardson

Research output: Contribution to journalArticlepeer-review

Abstract

Diffusely infiltrating gliomas are among the most common central nervous system tumors in adults. Over the past decade, the subcategorization of these tumors has changed to include both traditional histologic features and more recently identified molecular factors. However, one molecular feature that has yet to be integrated is the presence/absence of chromosomal instability (CIN). Herein, we use global methylation profiling to evaluate a reference cohort of IDH-mutant astrocytomas with and without prior evidence of CIN (n = 42), and apply the resulting methylation-based characteristics to a larger test cohort of publicly-available IDH-mutant astrocytomas (n = 245). We demonstrate that IDH-mutant astrocytomas with evidence of CIN cluster separately from their chromosomally-stable counterparts. CIN cases were associated with higher initial histologic grade, altered expression patterns of genes related to CIN in other cancers, elevated initial total copy number burden, and significantly worse progression-free and overall survival. In addition, in a grade-for-grade analysis, patients with CIN-positive WHO grade 2 and 3 tumors had significantly worse survival. These results suggest that global methylation profiling can be used to discriminate between chromosomally stable and unstable IDH-mutant astrocytomas, and may therefore provide a reliable and cost-effective method for identifying gliomas with chromosomal instability and resultant poor clinical outcome.

Original languageEnglish (US)
Article number32
JournalActa Neuropathologica Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Astrocytoma
  • Chromosomal instability
  • Copy number variation
  • Glioblastoma
  • Glioma
  • IDH-mutation
  • Methylation profiling

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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