Sarcomas display considerable histological diversity, with over 70 recognized subtypes, which complicates precise classification. Although specific genetic alterations can aid pathological evaluation, routine diagnostic workflows rarely incorporate large-scale molecular profiling. In this study, we explored the utility of whole genome sequencing (WGS) to enhance the clinical management of sarcoma patients by detecting diagnostic markers, therapeutically actionable variants, and underlying hereditary predispositions. Tumor and germline DNA from 83 patients with suspected sarcomas at a tertiary referral center were subjected to WGS, and patients were followed prospectively to determine the impact on clinical decisions. In 14% of cases (12/83), genomic analysis prompted a revision of the initial diagnosis, leading to treatment modifications in eight patients. Notably, all these cases had undergone multiple tissue sampling procedures and detailed immunohistopathological evaluations by both regional and expert pathologists before WGS. Additionally, potential therapeutic biomarkers were identified in 30 patients, and pathogenic germline variants were observed in seven. Overall, unbiased WGS enables the identification of genomic features with direct implications for patient care. Considering the diagnostic challenges and the urgent need for novel therapeutic options in sarcoma, WGS provides a valuable enhancement to conventional diagnostic approaches.
