New Research Article from William Cross PhD.
William Cross, Ph.D. our board member from the UCL Cancer Center in London has been gracious enough to share his recently published article on:
A genetic model for central chondrosarcoma
evolution correlates with patient outcome
It is William’s hope that others will emulate and replicate the study and in time we can begin testing and stratifying patients using these markers: IDH1, IDH2, and TERT mutations.
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 favour‑able 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.