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case_images: Case clinical history. (A) Images from magnetic resonance imaging (MRI) brain scans from the meningioma lung metastases case are presented here. (B) Graphical timeline plot summarizing the sample collection, treatment, and clinical event history for this case.
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case_images: A brain MRI scan depicted a large bifrontal mass lesion ( Figure 1A ) which straddled the midline on either side of the interhemispheric fissure in the anterior cranial fossa, measuring 7cm in width and almost 6cm in the anteroposterior dimension, consistent with a meningioma. The interval increased to 6 months until the end of 2016 when a brain MRI scan demonstrated a local recurrence ( Figure 1A ). Diagnostic imaging with a CT scan of his thorax, abdomen, and pelvis with contrast performed during this admission demonstrated multiple bilateral pulmonary masses ( Figure 1A ). WGS was performed on samples taken from the primary tumor resection (M1-T), the re-excised recurrent tumor (M2-T) after adjuvant radiation therapy, the lung metastases (M3-T) before treatment with sunitinib, and one paired blood sample for tumor-normal analysis ( Figure 1B ;  Supplementary Figure S1 ).
case_images: Genome-wide characterization of meningioma lung metastases tumor samples. (A) Somatic copy number log ratio (tumor over normal) coverage plots for the primary tumor (M1-T), recurrence (M2-T), and lung metastases (M3-T). The red horizontal line indicates a diploid log ratio reference. (B) Lolliplot of a recurrent missense mutation Q389* (orange dot) identified in the Merlin protein encoded by the NF2 gene from the WGS data (C) Circos plots of genome-wide chromosomal structural variation [DEL: deletions (blue dots); DUP: duplications (orange dots); INV: inversions (green dots); inter chromosomal translocations (TRA) indicated by black center line links] across all tumor samples. (D) Bar chart of the number of somatic SVs detected in each tumor sample with the colors indicating SV type [DEL (blue), DUP (orange), INV (green), TRA (pink)]. (E) Summary of the nonsynonymous TMB estimates [log total per megabase (Mb)] for tumor samples (M1-T, M2-T, M3-T). (F) Stacked bar chart of the relative contribution (0-100) of the COSMIC reference mutational signatures (Signature 1-30) detected in each tumor sample (left-right) using the Signal (v2) mutational signature profiling framework.
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case_images: We used the Bi et al.'s genomic sequencing of high-grade meningioma tumor samples and Nassiri et al.'s molecular subgroups as a reference for molecular classification and characterization of the meningioma tumors profiled here ( Supplementary Figure S2 ). The genome-wide somatic copy number profiles were remarkably similar across all tumor sample timepoints ( Figure 2A ). In the NF2 gene, a C>T nonsense (stop gained) mutation was detected in the primary tumor (M1-T) and lung metastases (M3-T) at variant allele frequency (VAF) estimates of 32% and 100% ( Figures 2B, C ). Structural variant calling identified a large number of intrachromosomal inversions in both the primary tumor (n=114) and lung metastases (n=398) ( Figures 2D, E ) with few interchromosomal translocations (TRAs) identified. Nassiri et al. and Choundary et al. respectively. Next, the tumor mutational burden (TMB) was calculated as the total number of nonsynonymous somatic mutations divided by the exome region length in megabases (Mb) ( Figure 2F ). NF2-altered recurrent meningioma tumors ( Supplementary Figure S2 ). Next, in order to investigate which mutagenic process may have led to a stepwise increase in TMB and chromosomal instability with disease progression, we performed a mutational signature analysis of somatic single nucleotide variants ( Figure 2F ;  Supplementary Figure S3 ).
case_images: Clonal evolution in the meningioma lung metastases. (A) High-level graphical overview of clonal evolution analysis workflow. (B) Venn diagram of the nonsynonymous somatic mutation counts from all tumor samples. (C) Line plot of clonal prevalence (0-1.0) changes across all tumor sample timepoints (left to right). Five tumor clones [Clone #1 (dark green), #2 (orange), #3 (purple), #4 (pink), #5 (purple)] were identified using PyCloneVI. (D) Node tree plot shows the clonal ordering of the tumor clones from ClonEvol. (E) Fish plot shows a graphical representation of the clonal evolution across all tumor sample timepoints for the primary tumor (left), recurrence (middle), and lung metastases (right). (F) Heatmap of VAF (0-1.0) values for a subset of the total nonsynonymous somatic mutations for the primary meningioma (bottom), recurrence (middle), and lung metastases (top). The mutations were selected for heatmap visualization if they were classified as either a predicted driver mutation by the Cancer Genome Interpreter (CGI), annotated as a frequently mutated gene in high-grade meningioma (MNG) tumors, or if the mutation was present in 2 or more tumor samples. The mutations shown in the heatmap are sorted by PyCloneVI clone assignment. The mutations are additionally annotated by consequence type and canonical oncogenic pathway membership.
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case_images: NF2-altered recurrent meningioma tumors ( Supplementary Figure S2 ). Next, in order to investigate which mutagenic process may have led to a stepwise increase in TMB and chromosomal instability with disease progression, we performed a mutational signature analysis of somatic single nucleotide variants ( Figure 2F ;  Supplementary Figure S3 ). Figure 3A ;  Supplementary Figure S4 ). Five tumor clones (labeled Cluster/Clone #1 to #5) were detected across the primary meningioma, recurrence, and lung metastases sample timepoints ( Figure 3C ). Nonsynonymous predicted driver mutations in Clone #3 included NF2 (p.Q389*), as previously described above, BRCA2 (p.E51K), and SEC23B (p.G285V) ( Figure 3B ). The lung metastases were composed of Clone #3, Clone #1, and Clone #2 ( Figures 3D, E ). Table 1 ). The only predicted drug-responsive biomarkers detected were NF2 (p.Q389* mutation/copy number loss or deletion) and BRCA2 (p.E51K mutation) in Clone #3, present in all three tumors and SETD2 (p.S1885N mutation) present only in Clone #4 in the recurrence ( Figure 3F ).