Accurate prediction of central conventional CHondrosarcoma Risk and Outcome using MEthylation profiling: CHROME

Given the increasing use of DNA methylation profiling as a valuable tool in surgical pathology for tumour classification, we investigated its prognostic value in central conventional chondrosarcoma. We generated methylation data from 69 primary central conventional chondrosarcomas profiled with Illumina’s Human MethylationEPIC Array (850k sites), and identified methylation sites individually linked to patient outcome. A LASSO Cox regression model was applied to these methylation sites to identify an optimal set of 8 informative sites. With the regression coefficients of these methylation sites, we constructed a risk score that predicts central conventional CHondrosarcoma Risk Outcome from Methylation (CHROME). CHROME stratifies patients into High or Low risk groups for disease recurrence, onset of metastasis and disease-specific mortality. Survival analysis in an independent validation cohort (n=68) demonstrated strong discriminatory performance of CHROME, with complete separation of outcomes and no adverse events observed in the Low risk group. Overview of the clinico-pathological information showed that a low grade (ACT/G1) case with an event was correctly assigned to the High risk group, while 9 high grade cases without events were classified as Low risk. CHROME provides accurate risk stratification in central conventional chondrosarcoma and may represent a valuable tool for improving its prognostication and clinical management.