Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO
Victoria E. Clark1,
E. Zeynep Erson-Omay1,
Phillip B. Murray1,
Jennifer Moliterno Günel6,
Ahmet Okay Caglayan1,
A. Fatih Atik7,
Luis E. Kolb1,
Ryan M. Hebert1,
S. Bulent Omay1,
John D. Overton9,
Eric C. Holland10,
Matthew W. State11,
Joachim M. Baehring12,
Philip H. Gutin6,
Joseph M. Piepmeier13,
Cameron W. Brennan14,
M. Necmettin Pamir3,
Richard P. Lifton2,16,
James P. Noonan2,17,
Katsuhito Yasuno1, and
1 Departments of Neurosurgery and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, USA.
2 Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
3 Department of Neurosurgery, Acibadem University School of Medicine, Istanbul 34848, Turkey.
4 Dr. Orhan Öcalgiray Molecular Biology-Biotechnology and Genetics Research Center, Istanbul Technical University, Maslak 34469, Istanbul, Turkey.
5 Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
6 Department of Neurosurgery and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
7 Department of Neurosurgery, Marmara University School of Medicine, Istanbul 34854, Turkey.
8 Department of Genetics and Bioinformatics, Bahcesehir University, Istanbul 34353, Turkey.
9 Center for Genome Analysis, Yale School of Medicine, West Haven, CT 06516, USA.
10 Departments of Cancer Biology and Genetics, Neurosurgery, Neurology, and Surgery, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
11 Departments of Genetics and Psychiatry, Yale Program on Neurogenetics and Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA.
12 Departments of Neurology, Neurosurgery, and Internal Medicine, Yale Program in Brain Tumor Research and Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT 06510, USA.
13 Department of Neurosurgery, Yale Program in Brain Tumor Research and Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT 06510, USA.
14 Department of Neurosurgery and Brain Tumor Center, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
15 Department of Neurosurgery, Bahcesehir University School of Medicine, Istanbul 34349 Turkey.
16 Department of Internal Medicine, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
17 Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06520, USA.
18 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
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Fig. 1. Exome sequencing identifies meningioma subgroups based on mutually exclusive mutation profiles.|
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Fig. 2. Genomic architecture of meningiomas. (A) NF2, TRAF7, and SMO coding mutations along with recurrent AKT1E17K and KLF4K409Q variants reveal meningioma subtypes with mutually exclusive profiles. Analysis for chromosome 22 copy number is also shown. Each bar represents a grade I meningioma sample; 191 samples are depicted. (B) TRAF7 mutations, which are identified in 72 of 300 meningiomas analyzed, are clustered within its WD40 domains. The count of recurrent mutations, which are denoted by diamonds, is indicated. (C) The recurrent KLF4K409Q mutation is located within the first zinc finger domain, which makes direct DNA contact. (D) Circos plot of large-scale genomic abnormalities identified (blue: deletion, red: amplification). Whereas all NF2/chr22loss meningiomas (outer circles, n = 41, including n = 30 with coding NF2 mutations) show chromosome 22 loss, which is typically associated with further chromosomal abnormalities in grade II tumors (n = 11, including n = 8 with coding NF2 mutations), genomic stability is a hallmark of grade I non-NF2 tumors (inner circles, n = 36). (E) Along the skull base, NF2/chr22loss meningiomas originate from the lateral and posterior regions, whereas the vast majority of anterior and medial meningiomas are non-NF2 mutant. (F) Unsupervised hierarchical clustering of gene expression profiles defines two major benign meningioma subgroups, those with NF2/chr22loss and non-NF2 mutant tumors. Each subgroup reveals differential H3K27ac and gene expression profiles (figs. S10 to S14 and tables S5 to S8).|