A genetic model for central chondrosarcoma evolution correlates with patient outcome

William Cross 1, Iben Lyskjær 1 2, Tom Lesluyes 3, Steven Hargreaves 1, Anna-Christina Strobl 4, Christopher Davies 1 4, Sara Waise 3 5, Shadi Hames-Fathi 1, Dahmane Oukrif 1, Hongtao Ye 4, Fernanda Amary 4, Roberto Tirabosco 4, Craig Gerrand 6, Toby Baker 3, David Barnes 7, Christopher Steele 1, Ludmil Alexandrov 8, Gareth Bond 7; Genomics England Research Consortium; Paul Cool 9 10, Nischalan Pillay 1 4, Peter Van Loo # 11, Adrienne M Flanagan # 12 13

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.

Keywords: Cancer evolution; Chondrosarcoma; Genetics; Genomics; IDH1; IDH2; Sarcoma; TERT.

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• References

1. 1. Giuffrida AY, Burgueno JE, Koniaris LG, Gutierrez JC, Duncan R, Scully SP. Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. J Bone Joint Surg Am. 2009;91(5):1063–1072. doi: 10.2106/JBJS.H.00416. – DOI – PubMed
2. 1. Bovee J, Flanagan AM, Nielsen G, Akihiko Y, Bloem J. The WHO Classification of Tumours Editorial Board. WHO Classification of Tumours: Soft Tissue and Bone Tumours. IARC Press. 2020.
3. 1. Eefting D, Schrage YM, Geirnaerdt MJA, Le Cessie S, Taminiau AHM, Bovée JVMG, et al. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol. 2009;33(1):50–57. doi: 10.1097/PAS.0b013e31817eec2b. – DOI – PubMed
4. 1. Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer. 1977;40(2):818–831. doi: 10.1002/1097-0142(197708)40:2<818::AID-CNCR2820400234>3.0.CO;2-B. – DOI – PubMed
5. 1. Fromm J, Klein A, Baur-Melnyk A, Knösel T, Lindner L, Birkenmaier C, et al. Survival and prognostic factors in conventional central chondrosarcoma. BMC Cancer. 2018;18(1):849. doi: 10.1186/s12885-018-4741-7. – DOI – PMC – PubMed