Radiotherapy Response Prediction in Myxofibrosarcomas and Undifferentiated Soft Tissue Sarcomas Using DNA Methylation and Copy Number Profiling

BackgroundMyxofibrosarcoma (MFS) and undifferentiated soft tissue sarcoma (USTS) are common sarcoma subtypes with overlapping molecular features. Both are treated with neoadjuvant radiotherapy followed by surgery, yet radiotherapy response is variable and unpredictable. This study investigated DNA methylation and copy number variation (CNV) profiles obtained from pre-radiotherapy biopsies as predictive biomarkers of radiotherapy response.Patients and methodsPre-radiotherapy biopsies and post-radiotherapy resections were obtained from 49 patients (27 MFS, 22 USTS). Radiotherapy response was assessed on the resection specimens using the EORTC-STBSG 5-tier system; grades A-C (<10% viable tumor) were classified as responders, D-E (≥10% viable tumor) as non-responders. Genome-wide DNA methylation and CNV data were generated from the pre-radiotherapy biopsies using Illumina MethylationEPIC BeadChips and were correlated with response grades.ResultsDNA methylation profiling yielded evaluable results in 23/49 tumors (15 MFS, 8 USTS), with 9 responders and 14 non-responders. Unsupervised methylation clustering, incorporating public datasets, showed that MFS, USTS, and pleomorphic liposarcomas formed a single, heterogeneous cluster. Similarly, CNV profiles did not distinguish MFS from USTS. Methylation patterns did not significantly differ between responders and non-responders. CNV profiles were largely comparable between responders and non-responders, except of a significantly higher frequency of chromosome 11q24.1 loss in responders compared to non-responders (100% vs 33%; P = 0.0039).ConclusionsOur findings support the concept that MFS and USTS represent a spectrum of the same disease. We could not demonstrate the value of DNA methylation profiling in radiotherapy response prediction. However, 11q24.1 loss may represent a potential predictive biomarker and merits further validation.