A genetic model for central chondrosarcoma evolution correlates with patient outcome

Genome Medicine

Research

Craig Gerrand¹  Fernanda Amary²  Anna-Christina Strobl²  Hongtao Ye²  Roberto Tirabosco²  Gareth Bond³  David Barnes³  Steven Hargreaves⁴  William Cross⁴  Shadi Hames-Fathi⁴  Dahmane Oukrif⁴  Christopher Steele⁴  Christopher Davies⁵  Nischalan Pillay⁵  Adrienne M. Flanagan⁵  Iben Lyskjær⁶  Paul Cool⁷  Peter Van Loo⁸  Toby Baker⁸  Tom Lesluyes⁸  Sara Waise⁹  Ludmil Alexandrov^1,10 

[1] Bone Tumour Unit, Royal National Orthopaedic Hospital, Stanmore, UK;Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK;Institute of Cancer and Genomic Sciences, Birmingham University, Birmingham, UK;Research Department of Pathology, University College London, UCL Cancer Institute, London, UK;Research Department of Pathology, University College London, UCL Cancer Institute, London, UK;Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK;Research Department of Pathology, University College London, UCL Cancer Institute, London, UK;Medical Genomics Research Group, University College London, UCL Cancer Institute, London, UK;Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, UK;Keele University, Keele, UK;The Francis Crick Institute, London, UK;The Francis Crick Institute, London, UK;Cancer Sciences Unit, University of Southampton, Southampton, UK;University of California, San Diego, USA;

关键词: Chondrosarcoma;    Sarcoma;    Genetics;    Genomics;    Cancer evolution;    IDH1;    IDH2;    TERT;   

DOI  :  10.1186/s13073-022-01084-0

 received in 2021-11-02, accepted in 2022-07-07,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundCentral conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations.MethodsIn this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings.ResultsIDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group.ConclusionsTumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2023

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