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A genetic model for central chondrosarcoma evolution correlates with patient outcome

Cross, William; Lyskjær, Iben; Lesluyes, Tom; Hargreaves, Steven; Strobl, Anna-Christina; Davies, Christopher; Waise, Sara; Hames-Fathi, Shadi; Oukrif, Dahmane; Ye, Hongtao; Amary, Fernanda; Tirabosco, Roberto; Gerrand, Craig; Baker, Toby; Barnes, David; Steele, Christopher; Alexandrov, Ludmil; Bond, Gareth; Cool, Paul; Pillay, Nischalan; Van Loo, Peter; Flanagan, Adrienne M.; Research Consortium, Genomics England

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Authors

William Cross

Iben Lyskjær

Tom Lesluyes

Steven Hargreaves

Anna-Christina Strobl

Christopher Davies

Sara Waise

Shadi Hames-Fathi

Dahmane Oukrif

Hongtao Ye

Fernanda Amary

Roberto Tirabosco

Craig Gerrand

Toby Baker

David Barnes

Christopher Steele

Ludmil Alexandrov

Gareth Bond

Nischalan Pillay

Peter Van Loo

Adrienne M. Flanagan

Genomics England Research Consortium



Abstract

BACKGROUND: Central 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. METHODS: In 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. RESULTS: IDH2-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. CONCLUSIONS: Tumours 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.

Journal Article Type Article
Acceptance Date Jul 7, 2022
Online Publication Date Aug 30, 2022
Publication Date Aug 30, 2022
Publicly Available Date May 30, 2023
Journal Genome Medicine
Electronic ISSN 1756-994X
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 14
Issue 99
DOI https://doi.org/10.1186/s13073-022-01084-0
Publisher URL https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01084-0

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