Identification of novel gene fusions in soft tissue sarcoma: real-world evidence

What is it about?

Soft tissue sarcomas (STS) exhibit profound molecular heterogeneity. While recurrent gene fusions hold significant diagnostic and therapeutic value—guiding treatment selection and identifying novel molecular targets—our understanding of their broader clinical implications remains limited We performed next-generation sequencing (NGS; FusionPlex Sarcoma v2, Archer™) and bioinformatic analysis (STAR v.2.7, Arriba) on formalin-fixed paraffin-embedded (FFPE) core needle biopsy specimens. The cohort consisted of patients enrolled in a phase II clinical trial (NCT03651375) who received preoperative chemoradiotherapy according to the UNRESARC protocol. The analysed cohort comprised nine adult patients (median age 66 years; range 44–73) diagnosed with undifferentiated pleomorphic sarcoma (UPS; n = 3), malignant peripheral nerve sheath tumour (MPNST; n = 3), myxofibrosarcoma (MFS; n = 2), and leiomyosarcoma (LMS; n = 1), predominantly high-grade (G3; 5/9) and extremity-localised (6/9). Gene fusions were detected in one-third of patients (3/9), exclusively in G3 tumours. Specifically, we identified an SGSH-PRKCA fusion in MFS (thigh), a LINC01133-OGA fusion in MPNST (thorax), and a concurrent JAZF1-MYH7B (chr7:27995037 intronic-chr20:33563203 exon/splice-site, out-of-frame but preserving myosin domains) with a PRKCA-associated intergenic rearrangement (chr1, retaining C1/kinase domains) in UPS (upper back). Notably, the SGSH-PRKCA and JAZF1-MYH7B pairs have not been previously described in the literature for these STS subtypes. Fusion-positive (F1) cases showed stable radiological disease (RECIST 1.1 SD) and EORTC C/D pathological responses with 5–20% residual viable tumour, whereas fusion-negative (F0) cases showed a wider range of radiological and pathological outcomes, including partial response, progression, and stable disease. Our analysis suggests that broad genomic profiling may provide complementary molecular information in diagnostically challenging cases managed at specialised sarcoma centres, particularly when morphology and immunohistochemistry are insufficient. In the present series, however, the detected rearrangements did not alter systemic treatment, and the data do not support claims of prognostic, predictive, or therapeutic actionability.

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Photo by Sangharsh Lohakare on Unsplash

Photo by Sangharsh Lohakare on Unsplash

Why is it important?

Soft tissue sarcoma (STS) is characterised by profound molecular heterogeneity and encompasses over 100 recognised histological subtypes, with a five-year overall survival (OS) of approximately 16–25% in advanced disease. Canonical gene fusions, present in 33–50% of sarcomas, provide diagnostic and, in selected subtypes, prognostic information; however, their predictive value with respect to conventional cytotoxic chemotherapy remains unestablished. Conventional diagnostic techniques such as FISH and RT-PCR are restricted to a predefined panel of target genes and are labour-intensive, whereas RNA-based next-generation sequencing (NGS) enables simultaneous detection of known and novel rearrangements from limited FFPE material. In this nine-patient adult cohort treated with standard neoadjuvant doxorubicin–ifosfamide within the UNRESARC phase II trial (NCT03651375), targeted mRNA sequencing identified gene fusions in 33.3% (3/9) of cases, all confined to G3 tumours; these findings did not alter the treatment delivered. The detected rearrangements—SGSH-PRKCA, LINC01133-OGA, and concurrent JAZF1-MYH7B/PRKCA-associated rearrangements—are of unknown functional and clinical significance and should be regarded as exploratory. Larger, prospectively annotated cohorts with orthogonal validation are required before any prognostic or predictive inference can be drawn.

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