Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations
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1 Genomic sequencing of meningiomas identifies oncogenic SMO and AKT mutations Priscilla K. Brastianos*; Peleg M. Horowitz*; Sandro Santagata; Robert T. Jones; Aaron McKenna; Gad Getz; Keith L. Ligon; Emanuele Palescandolo; Paul Van Hummelen; Matthew D. Ducar; Alina Raza; Ashwini Sunkavalli; Laura E. MacConaill; Anat O. Stemmer-Rachamimov; David N. Louis; William C. Hahn**; Ian F. Dunn**; Rameen Beroukhim** Supplementary Material Table of Contents Supplementary Note. Human Subjects Research 2 Supplementary Table. Cohort demographics. 3 Supplementary Table 2. Genes sequenced in the Validation set. Supplementary Table 3. Rearrangements in WGS samples. Supplementary Table 4. All mutated genes and significance. Supplementary Table 5. Samples and their individual mutations. separate excel file separate excel file separate excel file separate excel file Supplementary Table 6. Sequenom hme validation of AKT and SMO mutations 4 Supplementary Figure. Mutational subtypes. 5 Supplementary Figure 2. Comparison of low and high-grade tumors. 6 Supplementary Figure 3. Broad SCNA analysis. 7 Supplementary Figure 4. Additional rearrangements. 8 Supplementary Figure 5. Mutations in selected genes. 9
2 Supplementary Note: Human Subjects Research This study was reviewed and approved by the human subjects institutional review boards of the Dana-Farber Cancer Institute, Brigham and Women s Hospital, and the Broad Institute of Harvard and MIT. Written informed consent was obtained from all participants. Representative fresh-frozen blocks with estimated purity of 90% were selected from 65 patients with meningiomas. Three study pathologists (SS/DL/ASR) reviewed the histopathologic diagnosis, grade and purity of each tumor. We performed whole-exome sequencing in 6 meningiomas and whole-genome sequencing in meningiomas. To validate mutations identified in the discovery set, we performed focused sequencing on a validation cohort consisting of an additional 30 grade I meningiomas. We also assembled an extrapolation cohort of 5 grade II and 3 grade III meningiomas in order to compare genetic aberrations of low- and high-grade tumors. We subsequently obtained IRB approval for collection of independent archival paraffinembedded meningioma samples from the Brigham and Women s Hospital Pathology Department. We identified 95 samples from patients that did not overlap with our cohort of 65 tumors, resected between 5 and 202. Forty-nine of these were higher-grade meningiomas. The samples were assayed for SMO and AKT mutations using Sequenom s homogeneous Mass-Extend (hme) Genotyping system (Sequenom, Inc. San Diego, CA). 2
3 Supplementary Table. Demographic and pathologic characteristics of the discovery and validation cohorts. Discovery Validation Extrapolation All Samples Total Grade I % Grade II % Grade III % MIB- (%) 3.% 4.% Grade II: 9.8% 6.2% Grade III: 26.6% Histopathological Subtype Fibroblastic 8 (47.%) (36.7%) N/A Transitional 5 (29.4%) 8 (26.7%) N/A Meningothelial 2 (.8%) 0 (33.3%) N/A Angiomatous 2 (.8%) (3.3%) N/A Location Convexity (64.7%) 5 (%) 7 (38.9%) 3 (47.7%) Falco-Tentorial 3 (7.6%) 7 (23.3%) 7 (38.9%) 7 (26.2%) Skull Base 3 (7.6%) 8 (26.7%) 3 (6.7%) 4 (2.5%) Intraventricular 0 (0%) 0 (0%) (5.6%) (.5%) Age (at resection) 5 (28-7) 58 (28-86) 60.5 (40-85) 58 (28-86) Gender Female 6 (94.%) 24 (80%) 3 (72%) 53 (8.5%) Male (5.9%) 6 (20%) 5 (27.8%) 2 (8.4%) Remote radiation exposure (5.9%) 3 (0%) 3 (2.4%) 7 (0.7%) Recent radiation treatment 0 (0%) (2.9%) 3 (2.4%) 4 (6.2%) Convexity: Frontal, Frontoparietal, Parietal, Frontotemporal, Temporal, Occipital Falcotentorial: Parasagittal, Falcine, Parafalcine, Torcular, and Tentorial Skull Base: Olfactory Groove, Sphenoid Wing, Clinoidal, Planum Sphenoidale, Cavernous Sinus, Petrous Apex, CP Angle, Other Posterior Fossa, Foramen Magnum, and Cervical (C- C2) Intraventricular: Right Lateral Ventricular 3
4 Supplementary Table 6. Mutations in AKT (E7K) and SMO (L42F or W535L) in 46 additional grade I and 49 grade II/III tumors. F: forward, R: reverse probe Assay Mutation observed Grade Histopathology Location Location Category Other AKT_E7K_chr4: C>T_hg9_h_F high confidence III Anaplastic Falcine Falco-tentorial Recurrent AKT_E7K_chr4: C>T_hg9_h_R high confidence AKT_E7K_chr4: C>T_hg9_h_F high confidence I Meningothelial Suprasellar/Left optic canal Skull Base AKT_E7K_chr4: C>T_hg9_h_R high confidence SMO_L42F_chr7: C>T_hg9_h_F high confidence I Transitional Olfactory groove/planum sphenoidale Skull Base SMO_L42F_chr7: C>T_hg9_h_R high confidence AKT_E7K_chr4: C>T_hg9_h_F high confidence I Meningothelial Right sphenoid wing Skull Base AKT_E7K_chr4: C>T_hg9_h_R high confidence 4
5 a b Nonsilent Mutation Rate (per Mb) NF2-mutated NF2: Focally altered NF2-wildtype Not focally altered c d Supplementary Figure. Detailed spectrum of coding-region mutation subtypes in meningioma. (a) The entire discovery set (n=7) shows a predominance of spontaneous deaminations in CpG context (yellow, right columns). (b) Mutation rates do not differ significantly between samples with (n=0) or without (n=7) NF2 focal alterations (mean +/- SEM). (c) Samples with focal NF2 aberrations and (d) samples without focal NF2 alterations do not differ appreciably in the spectrum of their mutation subtypes. 5
6 a Chr X Validation Grade I Extrapolation Grade II III b Percentage of genome altered by SCNAs c Mutations in 645 sequenced genes p = Validation Grade I p = 0.04 Validation Grade I 2.8 Extrapolation Grades II-III Extrapolation Grades II-III Supplementary Figure 2. Higher-grade meningiomas harbor more genetic alterations than their grade I counterparts. (a) Copy-number heat-map for tumors in the validation cohort (red: gain, blue: loss). Samples are in the same order as in Figure 3. (b) Percentage of the genome affected by somatic copy-number alterations and (c) number of mutations are significantly higher in grade II-III tumors (mean +/- SEM). 6
7 Supplementary Figure 3. Significant broad somatic copy-number alterations (SCNAs) in meningiomas. GISTIC 2.0 broad analysis was used with SegSeq copy-number data to determine the significance of recurrent events in (a) the discovery set of 7 grade I meningiomas and (b) the 8 grade II-III tumors of the validation set. Chr22 loss is the most frequent and significant broad SCNA (q=0). 7
8 a b c d e f g h i CHEK2 Supplementary Figure 4. Somatic rearrangements in the remaining whole-genome sequenced meningiomas (see Figure 2). Circos plots show the CNAs (inner ring heatmap) and intra-chromosomal (green) and inter-chromosomal (purple) rearrangements in eight whole-genome sequenced meningiomas (a-h). Samples a-e have focal alterations in NF2, while samples f-h do not. (i) A rearrangement in a grade III meningioma in the validation set causes fusion of CHEK2 with a neighboring gene on chr22. There may be additional translocations in this tumor, as only 645 genes were sequenced in this sample. 8
9 pq8fs pe32* p39translocation pw4* pr57* pr57* pk80splice pv8splice pv8splice pq2q py44* py44fs pk49splice pk49splice pysplice pysplice pr60fs pr96* prsplice prsplice pl24fs pk227fs pq324* pr34* pe386fs pi47fs pe434* ps444fs pi52fs Silent Missense Splice Site Nonsense Frame Shift In Frame Indel Translocation MERL NF2 00 pl42f 2 pw535l 3 pw535l FERM Glu rich pg277r pv59m Nuclear loc. signal JARD2 JARID2 JmjN ARID GSGFP motif JmjC SMO Extracellular FZ Transmembrane Poly Ser Cytoplasmic ph86y pe892d ps446g pe7k pe7k pe7k pe7k pe7k FACD2 FANCD2 Interacts w/fance Interacts w/brca2 AKT PH Protein kinase ATP AGC kinase C term pd279v 3 4 MTOR pr374q FAT PI3K/PI4K FATC SNF5 SMARCB DNA binding 2x approx. tandem rpts. MYC binding Interacts w/pppr5a pc267* pd457e pd723y CLM6 CDC pg33fs pg33fs Extracellular Ig like V type Pro rich Transmembrane Cytoplasmic p59translocation 00 p34translocation NEGR Ig like C2 type Ig like C2 type 2 Ig like C2 type 3 pa772a pl82r pl82r pl82r pl82r pr86c pr86c pr86c KDM5C JmjN ARID PHD type JmjC PHD type 2 RGPD Potential RanBD Poly Ser RanBD 2 GRIP Supplementary Figure 5. Locations of somatic mutations, insertions/deletions, and rearrangements in NF2 and other genes. 9
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