What is it about?
Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion; given limited effective treatments and marked heterogeneity, there is a need to identify therapeutic targets, a task facilitated by next-generation sequencing (NGS) in clinical practice. We report 2 STS pts with the diagnosis of UPS, G3 - each treated in a clinical trial (NCT03651374) with UNRESARC protocol consisting of neoadjuvant chemotherapy (CHT), radiotherapy, and surgical resection. Biopsy samples from each patient were subjected to NGS with the TruSight™ Oncology 500 assay (Illumina) and analysed in PierianDX (commercial software). 5 pathogenic alterations were identified: Case A: CCNE1 (6 copies) and MYC (3 copies) amplifications; Case B: CCND1 (3 copies), EGFR (3 copies) and FGFR1 (4 copies) amplifications. Amplifications of cell-cycle associated (CCNE1, CCND1) and apoptosis-related (MYC) genes contribute to uncontrolled proliferation and resistance to apoptosis, while amplifications in receptor tyrosine kinases (EGFR and FGFR1) activate pathways (RAS/MAPK and PI3K/AKT), involved in tumour growth and metastasis. In both patients, a poor pathological response, early local recurrence (LRFS of 9 months in both patients) and progressive disease (PD) when treated with first-line palliative CHT (PFS of 5 months in A and 4 months in B) were noted. All tumours demonstrated a low tumour mutation burden (TMB) (1.6–3.9 mut/Mb) and no microsatellite instability (MSI), explaining no sensitivity to immune checkpoint inhibitors.
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Why is it important?
NGS assays may enable accurate diagnosis and identify predictive biomarkers and novel therapeutic targets - of particular importance in poor-prognosis entities such as UPS. Our report is consistent with the literature classifying UPS as malignancy with a high frequency of CNAs and low TBM.
Perspectives
The present study characterises UPS by pervasive CNA with convergence on cell-cycle and receptor tyrosine kinase (RTK) signalling. In the two UPS cases observed, CCNE1 (6 copies), CCND1 (3 copies), MYC (3 copies), EGFR (3 copies) and FGFR1 (4 copies) gains were identified, with low tumour mutational burden (TMB 1.6–3.9 mut/Mb) and MSI stable status. These findings correspond with the CNA-dominant, low-immunogenic landscape reported in larger series (Wang et al. 2022; Roland et al. 2016; Saoud et al. 2025; Bui et al. 2019; Gounder et al. 2022).
Piotr Remiszewski
Maria Sklodowska- Curie National Research Institute of Oncology
Read the Original
This page is a summary of: Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message, Journal of Applied Genetics, December 2025, Springer Science + Business Media,
DOI: 10.1007/s13353-025-01036-5.
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DOI
Remiszewski, P., Tysarowski, A., Seliga, K.A. et al. Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message. J Appl Genetics (2025). https://doi.org/10.1007/s13353-025-01036-5
Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message
Remiszewski, P., Tysarowski, A., Seliga, K.A. et al. Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message. J Appl Genetics (2025). https://doi.org/10.1007/s13353-025-01036-5
The use of NGS in clinical practice
Remiszewski P, Tysarowski A, Seliga KA, Bobak K, Piątkowski J, Golik P, Spałek MJ, Szumera-Ciećkiewicz A, Wągrodzki M, Rutkowski P, Czarnecka AM. Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message. J Appl Genet. 2025 Dec 19. doi: 10.1007/s13353-025-01036-5. Epub ahead of print. PMID: 41413689.
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