Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas

Markus Bredel, Lluís Espinosa, Hyunsoo Kim, Denise M. Scholtens, Joseph P. McElroy, Rajani Rajbhandari, Wei Meng, Thomas M. Kollmeyer, Tathiane M. Malta, Michael A. Quezada, Griffith R. Harsh, Teresa Lobo-Jarne, Laura Solé, Aran Merati, Surya Nagaraja, Sindhu Nair, Jaclyn J. White, Nanda K. Thudi, Jessica L. Fleming, Amy WebbAtsushi Natsume, Seishi Ogawa, Ruthild G. Weber, Joan Bertran, S. Jaharul Haque, Bettina Hentschel, C. Ryan Miller, Frank B. Furnari, Timothy A. Chan, Anca Ligia Grosu, Michael Weller, Jill S. Barnholtz-Sloan, Michelle Monje, Houtan Noushmehr, Robert B. Jenkins, C. Leland Rogers, David R. MacDonald, Stephanie L. Pugh, Arnab Chakravarti

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Original languageEnglish (US)
Article number101082
JournalCell Reports Medicine
Volume4
Issue number6
DOIs
StatePublished - Jun 20 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • H3K27M mutation
  • IDH mutation
  • NFKBIA deletion
  • glioma
  • haploinsufficiency
  • methylome
  • nomogram
  • tumor suppressor

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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