Cancer. 2025 Jun 15. 131(12): e35937
Adrian Schmid,
Anja E Eisenhardt,
Balazs Bogner,
Alexander Runkel,
Ute Lausch,
Thomas Pauli,
Laura N Antolini,
Anika Boneberg,
Jurij Kiefer,
Peter Bronsert,
Melanie Boerries,
Steffen U Eisenhardt,
David Braig.
BACKGROUND: Myxoid liposarcomas (MLS) are rare malignant mesenchymal tumors characterized by specific translocations t(12;16) and t(12;22) with limited additional driver mutations, most notably in PIK3CA and the TERT promoter. PIK3CA is considered a promising therapeutic target. However, effective treatments require the uniform presence of mutation throughout the tumor. Therefore, this study evaluated intratumoral heterogeneity of driver mutations in MLS.
METHODS: In total, 170 samples from 20 tumors (12 patients) were analyzed using an MLS-specific next-generation sequencing (NGS) panel. This included detecting the t(12;16) and t(12;22) translocations and known driver mutations.
RESULTS: Patient-specific t(12;16) or t(12;22) translocations were detected in all 20 tumors (159 of 170 samples; 94%) and remained identical in primary tumors, recurrences, and metastases. TERT promoter mutations were identified in 17 of 20 tumors (85%) and were distributed similarly across samples. In contrast, PIK3CA mutations were present in only 66 of 170 samples (39%), with these and the remaining driver mutations localized only in subclones within individual tumors.
CONCLUSIONS: Therapies that target PIK3CA are unlikely to succeed because of its limited subclonal distribution. In contrast, the ubiquitous presence of t(12;16), t(12;22), and TERT promoter mutations across MLS tumors suggests that these are more effective therapeutic targets for future treatment strategies.
Keywords: clonal evolution; myxoid liposarcoma; next‐generation sequencing; soft tissue sarcoma; tumor heterogeneity