Whole Genome and Transcriptome Analysis of Anaplastic Meningioma. Patrick Tarpey Cancer Genome Project Wellcome Trust Sanger Institute

Transcription

1 Whole Genome and Transcriptome Analysis of Anaplastic Meningioma Patrick Tarpey Cancer Genome Project Wellcome Trust Sanger Institute

2 Outline Anaplastic meningioma compared to other cancers Whole genomes inform diagnosis Landscape of driver variants Identification of clinically relevant sub-types

3 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%)

4 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

5 Study Design Discovery cohort (whole genomes) Paired FF DNA Extension cohort (known cancer genes) Paired and unpaired, FF and FFPE

6 Discovery Cohort

7 Discovery Cohort

8 Extension Cohort Solid tumour panel (52,461 probes, 2.05 Mb) Copy number SNP introns SNP cytoscape Point mutations Coding exons from 366 genes (CGC) 333 probes targeting actionable loci (KRAS, BRAF, EGFR, ALK, KIT, TP53) TERT promoter SNP gwas gene fusions 7941 regions exons, 366 genes 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

9 Outline Anaplastic meningioma compared to other cancers Whole genomes inform diagnosis Landscape of driver variants Identification of clinically relevant sub-types

10 Whole Genomes: point mutations subs indels subs (snp id)

11 Whole Genomes: mutation burden Sanger Analysis Pipeline Core Sequencing Facility Fastq Raw Data Mapping BWA-mem Bam Coverage stats Copy Number Point Mutations Indels Gene fusions CNVkit Caveman vcf Pindel vcf 50bp trim Annotation: Vagrent Brass Downstream Analysis Identification of Driver mutations & cancer genes, subclonal mutations etc Report

12 Whole Genomes: mutation burden

13 Universal Patterns Of Selection In Cancer And Somatic Tissues Inigo Martincorena

14 AM (n=19) NF2

15 Outline Anaplastic meningioma compared to other cancers Whole genomes inform diagnosis Landscape of driver variants Identification of clinically relevant sub-types

16 Whole Genomes: atypical cases subs indels subs (snp id)

17 NF2 mut `` `

18 MSI NF2 wt `` `

19 NAB2- STAT6 NF2 wt `` `

20 NAB2- STAT6 NF2 wt `` `

21 EML4- ALK NF2 wt `` `

22 EML4- ALK NF2 wt `` `

23 Discovery Cohort

24 Outline Anaplastic meningioma compared to other cancers Whole genomes inform diagnosis Landscape of driver variants Identification of clinically relevant sub-types

25 Rearrangements Supplementary Figure S4 a b b No recurrent novel fusions Disruptive rearrangements in PBRM1 and RB1 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.

26 Copy Number Aggregate CN profiles from 18 genomes Multiple recurrent CN changes deletions: 1p, 6q, 14 and 22 Homozygous deletion: NF2 and CDKN2A

27 Drivers

28 Outline Anaplastic meningioma compared to other cancers Whole genomes inform diagnosis Landscape of driver variants Identification of clinically relevant sub-types

29 31 tumours, 28 patients

30 31 tumours, 28 patients 25 patients

31 31 tumours, 28 patients 25 patients 100% NF2 ARID1A, PBRM1 62% 50% 0% C1 C2 C1 C2

32 Acknowledgements