Whole Genome and Transcriptome
Analysis of Anaplastic Meningioma
Patrick TarpeyCancer Genome Project
Wellcome Trust Sanger Institute
• Anaplastic meningioma compared to other cancers
• Whole genomes inform diagnosis
• Landscape of driver variants
• Identification of clinically relevant sub-types
Outline
Meningioma
• Most common primary central nervous system tumours in adults
• Originate from the meningeal membrane covering the brain and spinal cord
• Classified as:
Grade 1: benign (70-80%)
Grade 2: atypical (5-20%)
Grade 3: malignant (1-3%)
Anaplastic Meningioma
• Presentation: progression of lower grade tumour or de novo
• Prognosis: poor, many cases inevitable recurrence
• Current insight:
Grade 1 and 2: well characterised
Grade 3: poorly understood, limited therapeutic options
Study Design
• Discovery cohort (whole genomes)Paired FF DNA
• Extension cohort (known cancer genes)Paired and unpaired, FF and FFPE
Discovery Cohort
Discovery Cohort
Extension Cohort
Point mutations
• Coding exons from 366 genes (CGC)
• 333 probes targeting actionable loci (KRAS, BRAF, EGFR, ALK, KIT, TP53)
• TERT promoter
Fusions
• 2462 probes targeting 29 fusions involving 11 genes
Copy number
• 1912 probes targeting 961 reference SNPs (1 SNP per 3Mb)
• 1114 probes targeting SNPs in frequently amplified genes
Solid tumour panel (52,461 probes, 2.05 Mb)
genefusions
SNPgwas
SNPcytoscape
SNPintrons
Copynumber
exons,366genes7941regions
• Anaplastic meningioma compared to other cancers
• Whole genomes inform diagnosis
• Landscape of driver variants
• Identification of clinically relevant sub-types
Outline
Whole Genomes: point mutations
subs
indels
subs (snp id)
Whole Genomes: mutation burden
Sanger Analysis
PipelineCore Sequencing Facility
MappingBWA-mem
Fastq Raw Data
Downstream AnalysisIdentification of Driver mutations & cancer genes, subclonal mutations etc
Bam Coverage stats
CopyNumber
CNVkit
Genefusions
PointMutations
Indels
Brass
Cavemanvcf
Pindelvcf
Annotation:Vagrent
50bptrim
Report
Whole Genomes: mutation burden
Universal Patterns Of Selection In Cancer And Somatic Tissues
Inigo Martincorena
AM (n=19)
NF2
• Anaplastic meningioma compared to other cancers
• Whole genomes inform diagnosis
• Landscape of driver variants
• Identification of clinically relevant sub-types
Outline
Whole Genomes: atypical cases
subs
indels
subs (snp id)
``̀`
NF2 mut
``̀`
NF2 wt
MS
I
``̀`
NAB2-
STAT6
NF2 wt
``̀`
NAB2-
STAT6
NF2 wt
``̀`
NF2 wt
EML4-
ALK
``̀`
NF2 wt
EML4-
ALK
Discovery Cohort
• Anaplastic meningioma compared to other cancers
• Whole genomes inform diagnosis
• Landscape of driver variants
• Identification of clinically relevant sub-types
Outline
Supplementary Figure S4
a
b
Supplementary Figure S4 | Rearrangement burden of anaplastic meningioma. (a) Rearrangement subtypes in
18 primary anaplastic meningioma genomes classified into four broad categories of structural variant. The horizontal
axis indicates sample number and the vertical axis shows the total number of rearrangements. (b) Comparison of
overall rearrangement burden in anaplastic meningioma with 11 other tumor types colour coded according to source
of data and analysis. Horizontal axis indicates cancer type and number of samples per cohort. Vertical axis shows
rearrangent number per sample. Box plot hinges demarcate the 25th to 75th centile with median indicated by the
middle horizonal line and whiskers extending to 1.5 times the interquartile range. Underlying violin plots show the full
range and distribution of rearrangement burden across each tumor cohort. WTSI, Wellcome Trust Sanger Institute.
Supplementary Figure S4
a
b
Supplementary Figure S4 | Rearrangement burden of anaplastic meningioma. (a) Rearrangement subtypes in
18 primary anaplastic meningioma genomes classified into four broad categories of structural variant. The horizontal
axis indicates sample number and the vertical axis shows the total number of rearrangements. (b) Comparison of
overall rearrangement burden in anaplastic meningioma with 11 other tumor types colour coded according to source
of data and analysis. Horizontal axis indicates cancer type and number of samples per cohort. Vertical axis shows
rearrangent number per sample. Box plot hinges demarcate the 25th to 75th centile with median indicated by the
middle horizonal line and whiskers extending to 1.5 times the interquartile range. Underlying violin plots show the full
range and distribution of rearrangement burden across each tumor cohort. WTSI, Wellcome Trust Sanger Institute.
Rearrangements
• No recurrent novel fusions
• Disruptive rearrangements in PBRM1 and RB1
Copy Number
Aggregate CN profiles from 18 genomes
• Multiple recurrent CN changes
deletions: 1p, 6q, 14 and 22
• Homozygous deletion: NF2 and CDKN2A
Drivers
• Anaplastic meningioma compared to other cancers
• Whole genomes inform diagnosis
• Landscape of driver variants
• Identification of clinically relevant sub-types
Outline
31 tumours, 28 patients
31 tumours, 28 patients 25 patients
100%
62%
C1 C2
50%
0%
C1 C2
NF2 ARID1A, PBRM1
31 tumours, 28 patients 25 patients
