TY - JOUR
T1 - A genetic model for central chondrosarcoma evolution correlates with patient outcome
AU - Genomics England Research Consortium
AU - Cross, William
AU - Lyskjær, Iben
AU - Lesluyes, Tom
AU - Hargreaves, Steven
AU - Strobl, Anna Christina
AU - Davies, Christopher
AU - Waise, Sara
AU - Hames-Fathi, Shadi
AU - Oukrif, Dahmane
AU - Ye, Hongtao
AU - Amary, Fernanda
AU - Tirabosco, Roberto
AU - Gerrand, Craig
AU - Baker, Toby
AU - Barnes, David
AU - Steele, Christopher
AU - Alexandrov, Ludmil
AU - Bond, Gareth
AU - Cool, Paul
AU - Pillay, Nischalan
AU - Loo, Peter Van
AU - Flanagan, Adrienne M.
N1 - Funding Information:
We are grateful to the Biobank Team at the RNOH and RJAH, and all healthcare workers who cared for the patients. We specifically wish to thank the patients for engaging in our research. We acknowledge the work of the Genomics England research consortium: John Ambrose1; Prabhu Arumugam1; Roel Bevers1; Marta Bleda1; Freya Boardman-Pretty1,2; Christopher Boustred1; Helen Brittain1; Mark Caulfield1,2; Georgia Chan1; Greg Elgar1,2; Tom Fowler1; Adam Giess1; Angela Hamblin1; Shirley Henderson1,2; Tim Hubbard1; Rob Jackson1; Louise Jones1,2; Dalia Kasperaviciute1,2; Melis Kayikci1; Athanasios Kousathanas1; Lea Lahnstein1; Sarah Leigh1; Ivonne Leong1; Javier Lopez1; Fiona Maleady-Crowe1; Meriel McEntagart1; Federico Minneci1; Loukas Moutsianas1,2; Michael Mueller1,2; Nirupa Murugaesu1; Anna Need1,2; Peter O’Donovan1; Chris Odhams1; Christine Patch1,2; Mariana Buongermino Pereira1; Daniel Perez-Gil1; John Pullinger1; Tahrima Rahim1; Augusto Rendon1; Tim Rogers1; Kevin Savage1; Kushmita Sawant1; Richard Scott1; Afshan Siddiq1; Alexander Sieghart1; Samuel Smith1; Alona Sosinsky1,2; Alexander Stuckey1; Mélanie Tanguy1; Ana Lisa Taylor Tavares1; Ellen Thomas1,2; Simon Thompson1; Arianna Tucci1,2; Matthew Welland1; Eleanor Williams1; Katarzyna Witkowska1,2; Suzanne Wood1,2. 1. Genomics England, London, UK 2. William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Cancer evolution
KW - Chondrosarcoma
KW - Genetics
KW - Genomics
KW - IDH1
KW - IDH2
KW - Sarcoma
KW - TERT
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U2 - 10.1186/s13073-022-01084-0
DO - 10.1186/s13073-022-01084-0
M3 - Article
C2 - 36042521
AN - SCOPUS:85136986778
VL - 14
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 99
ER -