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

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 g...

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Published in:Cell reports. Medicine 2023-06, Vol.4 (6), p.101082, Article 101082
Main Authors: Bredel, Markus, Espinosa, Lluís, Kim, Hyunsoo, Scholtens, Denise M., McElroy, Joseph P., Rajbhandari, Rajani, Meng, Wei, Kollmeyer, Thomas M., Malta, Tathiane M., Quezada, Michael A., Harsh, Griffith R., Lobo-Jarne, Teresa, Solé, Laura, Merati, Aran, Nagaraja, Surya, Nair, Sindhu, White, Jaclyn J., Thudi, Nanda K., Fleming, Jessica L., Webb, Amy, Natsume, Atsushi, Ogawa, Seishi, Weber, Ruthild G., Bertran, Joan, Haque, S. Jaharul, Hentschel, Bettina, Miller, C. Ryan, Furnari, Frank B., Chan, Timothy A., Grosu, Anca-Ligia, Weller, Michael, Barnholtz-Sloan, Jill S., Monje, Michelle, Noushmehr, Houtan, Jenkins, Robert B., Rogers, C. Leland, MacDonald, David R., Pugh, Stephanie L., Chakravarti, Arnab
Format: Article
Language:English
Subjects:
Brain Neoplasms - genetics
Child
Epigenome
glioma
Glioma - genetics
Glioma - pathology
H3K27M mutation
haploinsufficiency
Haploinsufficiency - genetics
Humans
IDH mutation
Isocitrate Dehydrogenase
methylome
Mutation - genetics
NF-KappaB Inhibitor alpha - genetics
NFKBIA deletion
nomogram
tumor suppressor
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Summary: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. [Display omitted] •NFKBIA deletions exhibit a distinct pattern relative to other key genetic markers•NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation•NFKBIA deletions engender a transcriptome landscape reminiscent of H3K27M mutant glioma•NFKBIA deletions independently portend poor patient prognosis Bredel et al. characterize multiple adult diffuse glioma populations and reveal that haploinsufficient deletions of NFKBIA portend poor patient prognosis and align with epigenome and transcriptome landscapes that are antithetical to those induced by the IDH mutation and partly reminiscent of those induced by the H3K27M mutation in pediatric gliomas.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2023.101082