Epigenetic paradigm of DNA methylation for understanding the pathophysiology, diagnostics, and therapeutics in sarcomas

Sarcomas are heterogeneous malignant tumors originating from mesenchymal tissues, presenting substantial diagnostic and therapeutic challenges. The diverse genetic and epigenetic landscape provides significant heterogeneity and complexity to the disease, ultimately leading to poor outcomes for affected individuals, especially in metastatic diseases. As research in this field evolves, incorporating methylation profiling into routine clinical practice could significantly enhance the early diagnosis, risk stratification, and personalized treatment strategies for sarcoma patients. Moreover, the integration of advanced genetic techniques and ongoing upgradation in treatment strategies, predominantly those targeting methylation modifications, may lead to improved survival outcomes in sarcomas. We conducted a structured literature review using PubMed, Scopus, Embase, Google Scholar, and Web of Science, encompassing publications up to 30 November 2024. The search focused on DNA methylation in sarcoma pathogenesis, diagnostics, and therapeutics. Relevant articles were screened, and key findings were synthesized thematically. In this review, we provide a comprehensive insight into the role of DNA methylation in promoting sarcomas. We emphasize subtype-associated methylation patterns in sarcomas and their value as prognostic and diagnostic biomarkers, revealing their synergistic effects with the existing treatment regimens. Despite having preclinical outcomes, the translation of these therapies into clinical practice remains a challenge.