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Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

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  • Sam Behjati

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge
    Corpus Christi College)

  • Patrick S. Tarpey

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Kerstin Haase

    (The Francis Crick Institute)

  • Hongtao Ye

    (Royal National Orthopaedic Hospital NHS Trust)

  • Matthew D. Young

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Ludmil B. Alexandrov

    (Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory)

  • Sarah J. Farndon

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    UCL Great Ormond Street Institute of Child Health)

  • Grace Collord

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • David C. Wedge

    (Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Roosevelt Drive)

  • Inigo Martincorena

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Susanna L. Cooke

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Helen Davies

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • William Mifsud

    (UCL Great Ormond Street Institute of Child Health)

  • Mathias Lidgren

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Sancha Martin

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Calli Latimer

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Mark Maddison

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Adam P. Butler

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Jon W. Teague

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Nischalan Pillay

    (Royal National Orthopaedic Hospital NHS Trust
    University College London Cancer Institute)

  • Adam Shlien

    (The Hospital for Sick Children)

  • Ultan McDermott

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • P. Andrew Futreal

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    MD Anderson Cancer Center, University of Texas)

  • Daniel Baumhoer

    (Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, University of Basel)

  • Olga Zaikova

    (Oslo University Hospital)

  • Bodil Bjerkehagen

    (Oslo University Hospital)

  • Ola Myklebost

    (Oslo University Hospital
    University of Bergen)

  • M. Fernanda Amary

    (Royal National Orthopaedic Hospital NHS Trust)

  • Roberto Tirabosco

    (Royal National Orthopaedic Hospital NHS Trust)

  • Peter Van Loo

    (The Francis Crick Institute
    University of Leuven)

  • Michael R. Stratton

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Adrienne M. Flanagan

    (Royal National Orthopaedic Hospital NHS Trust
    University College London Cancer Institute)

  • Peter J. Campbell

    (Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge)

Abstract

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

Suggested Citation

  • Sam Behjati & Patrick S. Tarpey & Kerstin Haase & Hongtao Ye & Matthew D. Young & Ludmil B. Alexandrov & Sarah J. Farndon & Grace Collord & David C. Wedge & Inigo Martincorena & Susanna L. Cooke & Hel, 2017. "Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma," Nature Communications, Nature, vol. 8(1), pages 1-8, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15936
    DOI: 10.1038/ncomms15936
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    Cited by:

    1. Yang Zhou & Partho Sarothi Ray & Jianguo Zhu & Frank Stein & Mandy Rettel & Thileepan Sekaran & Sudeep Sahadevan & Joel I. Perez-Perri & Eva K. Roth & Ola Myklebost & Leonardo A. Meza-Zepeda & Andreas, 2024. "Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Yafei Jiang & Jinzeng Wang & Mengxiong Sun & Dongqing Zuo & Hongsheng Wang & Jiakang Shen & Wenyan Jiang & Haoran Mu & Xiaojun Ma & Fei Yin & Jun Lin & Chongren Wang & Shuting Yu & Lu Jiang & Gang Lv , 2022. "Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Georgia Zoumpoulidou & Carlos Alvarez-Mendoza & Caterina Mancusi & Ritika-Mahmuda Ahmed & Milly Denman & Christopher D. Steele & Maxime Tarabichi & Errin Roy & Lauren R. Davies & Jiten Manji & Camilla, 2021. "Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Nicholas Light & Mehdi Layeghifard & Ayush Attery & Vallijah Subasri & Matthew Zatzman & Nathaniel D. Anderson & Rupal Hatkar & Sasha Blay & David Chen & Ana Novokmet & Fabio Fuligni & James Tran & Ri, 2023. "Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Thomas R. W. Oliver & Lia Chappell & Rashesh Sanghvi & Lauren Deighton & Naser Ansari-Pour & Stefan C. Dentro & Matthew D. Young & Tim H. H. Coorens & Hyunchul Jung & Tim Butler & Matthew D. C. Nevill, 2022. "Clonal diversification and histogenesis of malignant germ cell tumours," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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