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Undifferentiated Sarcomas Develop Through Distinct Evolutionary Pathways

54 Pages Posted: 2 Jul 2018 Sneak Peek Status: Review Complete

See all articles by Christopher D. Steele

Christopher D. Steele

University College London

Maxime Tarabichi

Francis Crick Institute - Cancer Genomics Laboratory

Ludmil B. Alexandrov

Government of the United States of America - Theoretical Biology and Biophysics

Dahmane Oukrif

University College London - Research Department of Pathology

Hongtao Ye

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Matthew Fittall

Francis Crick Institute - Cancer Genomics Laboratory

Patrick Lombard

University College London - Research Department of Pathology

Inigo Martincorena

Wellcome Sanger Institute

Patrick S. Tarpey

Wellcome Genome Campus - Cancer Genome Project

Grace Collord

Wellcome Genome Campus - Cancer Genome Project

Sandra J. Strauss

University College London - Research Department of Pathology

Fitim Berisha

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Marnix Jansen

University College London - Research Department of Pathology

Sam Behjati

Wellcome Genome Campus - Cancer Genome Project

M Fernanda Amary

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Roberto Tirabosco

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Peter J. Campbell

Wellcome Genome Campus - Cancer Genome Project; Wellcome Trust Sanger Institute

Peter Van Loo

Francis Crick Institute - Cancer Genomics Laboratory

Adrienne M. Flanagan

University College London - Research Department of Pathology

Nischalan Pillay

University College London - Research Department of Pathology

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Abstract

Undifferentiated sarcomas (USARC) of adults are diverse, rare and aggressive soft tissue cancers. Recent efforts have confirmed that USARC exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the genomic basis of this structural complexity by integrating whole genome sequencing, ploidy analysis and methylation profiling of 53 USARC. We identified whole genome doubling as a prevalent and pernicious force in USARC tumourigenesis. Deconvolution of the complex copy number and rearrangement landscapes show distinct signatures associated with chromothripsis, early-haploidy, and successive whole-genome-doubling events, suggesting four divergent models of sarcoma development. We show similar distinct evolutionary tumourigenic pathways in different sarcoma subtypes from the Cancer Genome Atlas. Thirteen percent of tumours exhibited a hypermutator phenotype, opening new avenues for clinical management such as immunotherapy, whilst the period prior to and between genome doubling events may represent clinically relevant interventional points in USARC.

Suggested Citation

Steele, Christopher D. and Tarabichi, Maxime and Alexandrov, Ludmil B. and Oukrif, Dahmane and Ye, Hongtao and Fittall, Matthew and Lombard, Patrick and Martincorena, Inigo and Tarpey, Patrick S. and Collord, Grace and Strauss, Sandra J. and Berisha, Fitim and Jansen, Marnix and Behjati, Sam and Amary, M Fernanda and Tirabosco, Roberto and Campbell, Peter J. and Van Loo, Peter and Flanagan, Adrienne M. and Pillay, Nischalan, Undifferentiated Sarcomas Develop Through Distinct Evolutionary Pathways (2018). Available at SSRN: https://ssrn.com/abstract=3204559 or http://dx.doi.org/10.2139/ssrn.3204559
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Christopher D. Steele

University College London ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Maxime Tarabichi

Francis Crick Institute - Cancer Genomics Laboratory

1 Midland Road
London, NW1 1AT
United Kingdom

Ludmil B. Alexandrov

Government of the United States of America - Theoretical Biology and Biophysics

Los Alamos, NM 87545
United States

Dahmane Oukrif

University College London - Research Department of Pathology

Gower Street
London, WC1E 6BT
United Kingdom

Hongtao Ye

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Brockley Hill
Stanmore HA7 4LP
United Kingdom

Matthew Fittall

Francis Crick Institute - Cancer Genomics Laboratory

1 Midland Road
London, NW1 1AT
United Kingdom

Patrick Lombard

University College London - Research Department of Pathology

Gower Street
London, WC1E 6BT
United Kingdom

Inigo Martincorena

Wellcome Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Patrick S. Tarpey

Wellcome Genome Campus - Cancer Genome Project

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Grace Collord

Wellcome Genome Campus - Cancer Genome Project

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Sandra J. Strauss

University College London - Research Department of Pathology

Gower Street
London, WC1E 6BT
United Kingdom

Fitim Berisha

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Brockley Hill
Stanmore HA7 4LP
United Kingdom

Marnix Jansen

University College London - Research Department of Pathology

Gower Street
London, WC1E 6BT
United Kingdom

Sam Behjati

Wellcome Genome Campus - Cancer Genome Project

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

M Fernanda Amary

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Brockley Hill
Stanmore HA7 4LP
United Kingdom

Roberto Tirabosco

Royal National Orthopaedic Hospital NHS Trust - Department of Cellular and Molecular Pathology

Brockley Hill
Stanmore HA7 4LP
United Kingdom

Peter J. Campbell

Wellcome Genome Campus - Cancer Genome Project

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Peter Van Loo

Francis Crick Institute - Cancer Genomics Laboratory

1 Midland Road
London, NW1 1AT
United Kingdom

Adrienne M. Flanagan

University College London - Research Department of Pathology

Gower Street
London, WC1E 6BT
United Kingdom

Nischalan Pillay (Contact Author)

University College London - Research Department of Pathology ( email )

Gower Street
London, WC1E 6BT
United Kingdom

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