Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways

Christopher D Steele; Maxime Tarabichi; Dahmane Oukrif; Amy P Webster; Hongtao Ye; Matthew Fittall; Patrick Lombard; Iñigo Martincorena; Patrick S Tarpey; Grace Collord; Kerstin Haase; Sandra J Strauss; Fitim Berisha; Heli Vaikkinen; Pawan Dhami; Marnix Jansen; Sam Behjati; M Fernanda Amary; Roberto Tirabosco; Andrew Feber; Peter J Campbell; Ludmil B Alexandrov; Peter Van Loo; Adrienne M Flanagan; Nischalan Pillay

doi:10.1016/j.ccell.2019.02.002

Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways

Cancer Cell. 2019 Mar 18;35(3):441-456.e8. doi: 10.1016/j.ccell.2019.02.002.

Authors

Christopher D Steele¹, Maxime Tarabichi², Dahmane Oukrif¹, Amy P Webster³, Hongtao Ye⁴, Matthew Fittall², Patrick Lombard¹, Iñigo Martincorena⁵, Patrick S Tarpey⁵, Grace Collord⁵, Kerstin Haase², Sandra J Strauss⁶, Fitim Berisha⁴, Heli Vaikkinen⁷, Pawan Dhami⁸, Marnix Jansen⁹, Sam Behjati¹⁰, M Fernanda Amary⁴, Roberto Tirabosco⁴, Andrew Feber¹¹, Peter J Campbell¹², Ludmil B Alexandrov¹³, Peter Van Loo¹⁴, Adrienne M Flanagan¹⁵, Nischalan Pillay¹⁶

Affiliations

¹ Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK.
² Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1BF, UK.
³ Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.
⁴ Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
⁵ Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
⁶ Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK; Department of Oncology, University College London Hospital NHS Foundation Trust, London, NW1 2PG, UK.
⁷ Genomics and Genome Engineering Core Facility, CRUK-UCL Centre, Cancer Institute, University College London, London WC1E 6BT, UK; Research Department of Oncology, Cancer Institute, University College London, London WC1E 6BT, UK.
⁸ Genomics and Genome Engineering Core Facility, CRUK-UCL Centre, Cancer Institute, University College London, London WC1E 6BT, UK.
⁹ Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK; Department of Cellular Pathology, University College London Hospital NHS Foundation Trust, London NW1 2BU, UK.
¹⁰ Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
¹¹ Department of Targeted Intervention, Division of Surgery and Interventional Science, University College London, London WC1E 6BT, UK.
¹² Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK.
¹³ Department of Cellular and Molecular Medicine, University of California, San Diego 92093, USA.
¹⁴ Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1BF, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
¹⁵ Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK; Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
¹⁶ Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK; Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK. Electronic address: n.pillay@ucl.ac.uk.

Abstract

Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.

Keywords: cancer evolution; copy-number signatures; genomics; immuno-oncology; mutational signatures; sarcoma; tumor mutational burden.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation*
Evolution, Molecular
Gene Duplication
Gene Expression Profiling / methods*
Humans
Mutation
Ploidies
Prognosis
Sarcoma / genetics*
Sequence Analysis, DNA / methods*

Abstract

Publication types

MeSH terms

Grants and funding