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 Webb; Atsushi 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

doi:10.1016/j.xcrm.2023.101082

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Article number	101082
Journal	Cell Reports Medicine
Volume	4
Issue number	6
DOIs	https://doi.org/10.1016/j.xcrm.2023.101082
State	Published - Jun 20 2023

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2023.101082

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Bredel, M., Espinosa, L., Kim, H., Scholtens, D. M., McElroy, J. P., Rajbhandari, R., Meng, W., Kollmeyer, T. M., Malta, T. M., Quezada, M. A., Harsh, G. R., Lobo-Jarne, T., Solé, L., Merati, A., Nagaraja, S., Nair, S., White, J. J., Thudi, N. K., Fleming, J. L., ... Chakravarti, A. (2023). Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas. Cell Reports Medicine, 4(6), Article 101082. https://doi.org/10.1016/j.xcrm.2023.101082

Bredel, M, Espinosa, L, Kim, H, Scholtens, DM, McElroy, JP, Rajbhandari, R, Meng, W, Kollmeyer, TM, Malta, TM, Quezada, MA, Harsh, GR, Lobo-Jarne, T, Solé, L, Merati, A, Nagaraja, S, Nair, S, White, JJ, Thudi, NK, Fleming, JL, Webb, A, Natsume, A, Ogawa, S, Weber, RG, Bertran, J, Haque, SJ, Hentschel, B, Miller, CR, Furnari, FB, Chan, TA, Grosu, AL, Weller, M, Barnholtz-Sloan, JS, Monje, M, Noushmehr, H, Jenkins, RB, Rogers, CL, MacDonald, DR, Pugh, SL & Chakravarti, A 2023, 'Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas', Cell Reports Medicine, vol. 4, no. 6, 101082. https://doi.org/10.1016/j.xcrm.2023.101082

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

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.",

keywords = "H3K27M mutation, IDH mutation, NFKBIA deletion, glioma, haploinsufficiency, methylome, nomogram, tumor suppressor",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = jun,

day = "20",

doi = "10.1016/j.xcrm.2023.101082",

language = "English (US)",

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T1 - Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas

AU - Bredel, Markus

AU - Espinosa, Lluís

AU - Kim, Hyunsoo

AU - Scholtens, Denise M.

AU - McElroy, Joseph P.

AU - Rajbhandari, Rajani

AU - Meng, Wei

AU - Kollmeyer, Thomas M.

AU - Malta, Tathiane M.

AU - Quezada, Michael A.

AU - Harsh, Griffith R.

AU - Lobo-Jarne, Teresa

AU - Solé, Laura

AU - Merati, Aran

AU - Nagaraja, Surya

AU - Nair, Sindhu

AU - White, Jaclyn J.

AU - Thudi, Nanda K.

AU - Fleming, Jessica L.

AU - Webb, Amy

AU - Natsume, Atsushi

AU - Ogawa, Seishi

AU - Weber, Ruthild G.

AU - Bertran, Joan

AU - Haque, S. Jaharul

AU - Hentschel, Bettina

AU - Miller, C. Ryan

AU - Furnari, Frank B.

AU - Chan, Timothy A.

AU - Grosu, Anca Ligia

AU - Weller, Michael

AU - Barnholtz-Sloan, Jill S.

AU - Monje, Michelle

AU - Noushmehr, Houtan

AU - Jenkins, Robert B.

AU - Rogers, C. Leland

AU - MacDonald, David R.

AU - Pugh, Stephanie L.

AU - Chakravarti, Arnab

PY - 2023/6/20

Y1 - 2023/6/20

N2 - 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.

AB - 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.

KW - H3K27M mutation

KW - IDH mutation

KW - NFKBIA deletion

KW - glioma

KW - haploinsufficiency

KW - methylome

KW - nomogram

KW - tumor suppressor

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ER -

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

Abstract

Keywords

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