Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.
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 AKT1(E17K), 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.
Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, USA.
Victoria E
VE
Clark
E Zeynep
EZ
Erson-Omay
Akdes
A
Serin
Jun
J
Yin
Justin
J
Cotney
Koray
K
Ozduman
Timuçin
T
Avşar
Jie
J
Li
Phillip B
PB
Murray
Octavian
O
Henegariu
Saliha
S
Yilmaz
Jennifer Moliterno
JM
Günel
Geneive
G
Carrión-Grant
Baran
B
Yilmaz
Conor
C
Grady
Bahattin
B
Tanrikulu
Mehmet
M
Bakircioğlu
Hande
H
Kaymakçalan
Ahmet Okay
AO
Caglayan
Leman
L
Sencar
Emre
E
Ceyhun
A Fatih
AF
Atik
Yaşar
Y
Bayri
Hanwen
H
Bai
Luis E
LE
Kolb
Ryan M
RM
Hebert
S Bulent
SB
Omay
Ketu
K
Mishra-Gorur
Murim
M
Choi
John D
JD
Overton
Eric C
EC
Holland
Shrikant
S
Mane
Matthew W
MW
State
Kaya
K
Bilgüvar
Joachim M
JM
Baehring
Philip H
PH
Gutin
Joseph M
JM
Piepmeier
Alexander
A
Vortmeyer
Cameron W
CW
Brennan
M Necmettin
MN
Pamir
Türker
T
Kiliç
Richard P
RP
Lifton
James P
JP
Noonan
Katsuhito
K
Yasuno
Murat
M
Günel
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016515:Genes, Neurofibromatosis 2; D042822:Genomic Instability; D023281:Genomics; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008577:Meningeal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000072086:Smoothened Receptor; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics*
C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C486460:TRAF7 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt