A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome

Abstract

The treatment options for central chondrosarcoma are limited, and prognoses are generally unreliable. The presence and absence of mutations in IDH1, and IDH2 are defining events, and TERT mutations have been recently been associated with poor outcome. Despite this, molecular biomarkers are lacking. Here, analysing data from 356 patients, comprising results from whole genome sequencing (n=68), digital droplet PCR (n=346), and methylation arrays (n=57), we present a comprehensive genetic analysis of chondrosarcoma and suggest its clinical utility. Methylation profiles, TERT promoter mutations, genome doubling with prior haploidisation, and age at diagnosis of high grade, distinguish IDH1-mutant, IDH2-mutant and IDH wildtype tumours. The majority of IDH2-mutant tumours harbour TERT mutations, though a significant reduction in survival is only found in the less common mutational combination of IDH1 and TERT. We suggest that diagnostic testing for IDH1, IDH2 and TERT mutations could guide clinical monitoring and prognostication.

Distinct IDH1/2-associated Methylation Profile and Enrichment ofTP53andTERTMutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma

“…Further studies are needed to elucidate the mechanism and biological consequences of reduced and altered IDH-associated hypermethylation in DDCS. On the other hand, a recent study in central CS suggested that IDH-mutant tumors displayed significantly higher degree of global hypermethylation compared with IDH-mutant and IDH-wildtype tumors (40). Future studies looking into the differences in the methylation landscapes between IDH versus IDH-mutant DDCS may offer additional insights into the biology of different DDCS subtypes.…”

“…One study indicated that IDH/IDH mutations are associated with improved PFS but not OS in high-grade CS (39). Another recent study in central CS showed that although TERT mutations occur more frequently in IDH-mutant compared with IDH-mutant tumors, they are associated with worse survival in IDH-mutant but not IDH-mutant tumors (40).…”

Differentiated chondrosarcoma, variants of transformation of the sarcomatous component of the tumor

“…Аберрации гена IDH1, повидимому, встречаются примерно в 50 % случаев. Дедифференцированная хондросаркома у пожилых пациентов чаще локализуется в бедренной кости и тазе и связана с худшим прогнозом по сравнению с обычными вариантами данной опухоли [7,8].…”

“…Результаты CGH и LOH показали, что оба компонента потеряли одну и ту же копию 13-й хромосомы. Эти исследования подтвердили, что нехрящевой компонент высокой степени злокачественности возникает из предыдущего хрящевого компонента [7,9,10].…”