Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO

Victoria E. Clark, E. Zeynep Erson-Omay, Akdes Serin, Jun Yin, Justin Cotney, Koray Özduman, Timuçin Avşar, Jie Li, Phillip B. Murray, Octavian Henegariu, Saliha Yilmaz, Jennifer Moliterno Günel, Geneive Carrión-Grant, Baran Yilmaz, Conor Grady, Bahattin Tanrikulu, Mehmet Bakircioǧlu, Hande Kaymakçalan, Ahmet Okay Caglayan, Leman SencarEmre Ceyhun, A. Fatih Atik, Yaşar Bayri, Hanwen Bai, Luis E. Kolb, Ryan M. Hebert, S. Bulent Omay, Ketu Mishra-Gorur, Murim Choi, John D. Overton, Eric C. Holland, Shrikant Mane, Matthew W. State, Kaya Bilgüvar, Joachim M. Baehring, Philip H. Gutin, Joseph M. Piepmeier, Alexander Vortmeyer, Cameron W. Brennan, M. Necmettin Pamir, Türker Kiliç, Richard P. Lifton, James P. Noonan, Katsuhito Yasuno, Murat Günel

Research output: Contribution to journalArticle

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Abstract

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive - nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Original languageEnglish (US)
Pages (from-to)1077-1080
Number of pages4
JournalScience
Volume339
Issue number6123
DOIs
StatePublished - Mar 1 2013

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Meningioma
Mutation
Chromosomes, Human, Pair 22
Chromosomal Instability
Ubiquitin-Protein Ligases
Genomic Instability
Skull Base
Cerebrum
Phosphatidylinositol 3-Kinases
Brain Neoplasms
Transcription Factors

ASJC Scopus subject areas

  • General

Cite this

Clark, V. E., Erson-Omay, E. Z., Serin, A., Yin, J., Cotney, J., Özduman, K., ... Günel, M. (2013). Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science, 339(6123), 1077-1080. https://doi.org/10.1126/science.1233009

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. / Clark, Victoria E.; Erson-Omay, E. Zeynep; Serin, Akdes; Yin, Jun; Cotney, Justin; Özduman, Koray; Avşar, Timuçin; Li, Jie; Murray, Phillip B.; Henegariu, Octavian; Yilmaz, Saliha; Günel, Jennifer Moliterno; Carrión-Grant, Geneive; Yilmaz, Baran; Grady, Conor; Tanrikulu, Bahattin; Bakircioǧlu, Mehmet; Kaymakçalan, Hande; Caglayan, Ahmet Okay; Sencar, Leman; Ceyhun, Emre; Atik, A. Fatih; Bayri, Yaşar; Bai, Hanwen; Kolb, Luis E.; Hebert, Ryan M.; Omay, S. Bulent; Mishra-Gorur, Ketu; Choi, Murim; Overton, John D.; Holland, Eric C.; Mane, Shrikant; State, Matthew W.; Bilgüvar, Kaya; Baehring, Joachim M.; Gutin, Philip H.; Piepmeier, Joseph M.; Vortmeyer, Alexander; Brennan, Cameron W.; Pamir, M. Necmettin; Kiliç, Türker; Lifton, Richard P.; Noonan, James P.; Yasuno, Katsuhito; Günel, Murat.

In: Science, Vol. 339, No. 6123, 01.03.2013, p. 1077-1080.

Research output: Contribution to journalArticle

Clark, VE, Erson-Omay, EZ, Serin, A, Yin, J, Cotney, J, Özduman, K, Avşar, T, Li, J, Murray, PB, Henegariu, O, Yilmaz, S, Günel, JM, Carrión-Grant, G, Yilmaz, B, Grady, C, Tanrikulu, B, Bakircioǧlu, M, Kaymakçalan, H, Caglayan, AO, Sencar, L, Ceyhun, E, Atik, AF, Bayri, Y, Bai, H, Kolb, LE, Hebert, RM, Omay, SB, Mishra-Gorur, K, Choi, M, Overton, JD, Holland, EC, Mane, S, State, MW, Bilgüvar, K, Baehring, JM, Gutin, PH, Piepmeier, JM, Vortmeyer, A, Brennan, CW, Pamir, MN, Kiliç, T, Lifton, RP, Noonan, JP, Yasuno, K & Günel, M 2013, 'Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO', Science, vol. 339, no. 6123, pp. 1077-1080. https://doi.org/10.1126/science.1233009
Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Özduman K et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013 Mar 1;339(6123):1077-1080. https://doi.org/10.1126/science.1233009
Clark, Victoria E. ; Erson-Omay, E. Zeynep ; Serin, Akdes ; Yin, Jun ; Cotney, Justin ; Özduman, Koray ; Avşar, Timuçin ; Li, Jie ; Murray, Phillip B. ; Henegariu, Octavian ; Yilmaz, Saliha ; Günel, Jennifer Moliterno ; Carrión-Grant, Geneive ; Yilmaz, Baran ; Grady, Conor ; Tanrikulu, Bahattin ; Bakircioǧlu, Mehmet ; Kaymakçalan, Hande ; Caglayan, Ahmet Okay ; Sencar, Leman ; Ceyhun, Emre ; Atik, A. Fatih ; Bayri, Yaşar ; Bai, Hanwen ; Kolb, Luis E. ; Hebert, Ryan M. ; Omay, S. Bulent ; Mishra-Gorur, Ketu ; Choi, Murim ; Overton, John D. ; Holland, Eric C. ; Mane, Shrikant ; State, Matthew W. ; Bilgüvar, Kaya ; Baehring, Joachim M. ; Gutin, Philip H. ; Piepmeier, Joseph M. ; Vortmeyer, Alexander ; Brennan, Cameron W. ; Pamir, M. Necmettin ; Kiliç, Türker ; Lifton, Richard P. ; Noonan, James P. ; Yasuno, Katsuhito ; Günel, Murat. / Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. In: Science. 2013 ; Vol. 339, No. 6123. pp. 1077-1080.
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title = "Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO",
abstract = "We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5{\%} of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive - nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.",
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AU - Clark, Victoria E.

AU - Erson-Omay, E. Zeynep

AU - Serin, Akdes

AU - Yin, Jun

AU - Cotney, Justin

AU - Özduman, Koray

AU - Avşar, Timuçin

AU - Li, Jie

AU - Murray, Phillip B.

AU - Henegariu, Octavian

AU - Yilmaz, Saliha

AU - Günel, Jennifer Moliterno

AU - Carrión-Grant, Geneive

AU - Yilmaz, Baran

AU - Grady, Conor

AU - Tanrikulu, Bahattin

AU - Bakircioǧlu, Mehmet

AU - Kaymakçalan, Hande

AU - Caglayan, Ahmet Okay

AU - Sencar, Leman

AU - Ceyhun, Emre

AU - Atik, A. Fatih

AU - Bayri, Yaşar

AU - Bai, Hanwen

AU - Kolb, Luis E.

AU - Hebert, Ryan M.

AU - Omay, S. Bulent

AU - Mishra-Gorur, Ketu

AU - Choi, Murim

AU - Overton, John D.

AU - Holland, Eric C.

AU - Mane, Shrikant

AU - State, Matthew W.

AU - Bilgüvar, Kaya

AU - Baehring, Joachim M.

AU - Gutin, Philip H.

AU - Piepmeier, Joseph M.

AU - Vortmeyer, Alexander

AU - Brennan, Cameron W.

AU - Pamir, M. Necmettin

AU - Kiliç, Türker

AU - Lifton, Richard P.

AU - Noonan, James P.

AU - Yasuno, Katsuhito

AU - Günel, Murat

PY - 2013/3/1

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N2 - We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive - nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

AB - We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive - nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

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