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The chordoma genome Peter Campbell, Wellcome Trust Sanger Institute

The chordoma genome Peter Campbell, Wellcome Trust Sanger Institute. Chordoma. 1% of primary malignant bone tumours. 0.5-1/1000,000/year. 0 - 90 yrs : 55 , any age, Male to female ratio 2:1 . 32%. 33%. 29%. 37% metastasize 5% dedifferentiation Overall median survival ~7 years.

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The chordoma genome Peter Campbell, Wellcome Trust Sanger Institute

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  1. The chordoma genomePeter Campbell,Wellcome Trust Sanger Institute

  2. Chordoma • 1% of primary malignant bone tumours. • 0.5-1/1000,000/year. • 0 - 90 yrs: 55, any age, • Male to female ratio 2:1 32% 33% 29% • 37% metastasize • 5% dedifferentiation • Overall median survival ~7 years

  3. Chordoma H&E BRACHYURY

  4. Coding point mutations – 23 chordomas 1. Whole exome sequencing 2. Variant discovery 3. Validation and confirmation Sample ascertainment Sample QC Whole exome library preparation Massively parallel sequencing (Illumina) NGS data QC & filtering Whole exome mapping Normal –Tumour sequence comparison Raw variant discovery Variant annotation Variant selection Variant resequencing Roche 454 Somatic variant confirmation Define driver mutations Targeted resequencing studies Calculate prevalence

  5. Number of coding mutations per patient

  6. Mutations in known cancer genes

  7. PIK3CA mutations E545K M1043I

  8. Recurrently mutated genes

  9. Summary of exome data • 10-30 coding mutations per patient • No frequently mutated novel genes • Recurrent mutations in genes regulating histone modification • Recurrent mutations leading to activation of PI3K signalling

  10. Finding genomic rearrangements 500bp Chr 1 Chr 1 Chr 4 Chr 4

  11. Chordoma

  12. Other chordomas

  13. Hallmarks of chromothripsis • Massive genomic rearrangement in localised chromosomal regions • Whole chromosomes, chromosome arms or chromosome bands • Alternating copy number states • 2, 3 or occasionally 4 discrete states with many switches • Retention of heterozygosity in higher copy number state • Clustering of breakpoints • Ends essentially randomly joined in random orientation • Approx equal numbers of rearrangements with ‘deletion-type’, ‘tandem-duplication-type’ and ‘inverted’ orientation

  14. Catastrophe model Catastrophic chromosome breakage Non-homologous end joining

  15. Rearrangement screens in sarcoma

  16. Triple jeopardy – chordoma

  17. Role of inherited genetic factors

  18. SNP upstream of T (brachyury)

  19. Level of association – rs2305089

  20. SNP associated with T expression

  21. Conclusions • Chordomas show 10-30 coding mutations per patient • Frequent incidence of chromothripsis • Germline predisposition with brachyury SNP

  22. Acknowledgements • University College London • Adrienne Flanagan • Roberto Tibrabosco • Fernanda Amary • NischalanPillay • Chordoma Foundation • Josh Sommer Cancer Genome Project • Jose Tubio & Susie Cooke • Patrick Tarpey • David McBride • John Marshall & KeiranRaine • Adam Butler & Jon Teague • Lucy Stebbings & Catherine Leroy • Sarah O’Meara, Laura Mudie • Mike Stratton & Andy Futreal

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