Intratumoral heterogeneity of cancer driver genomic alterations in myxoid liposarcomas.

Abstract

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. 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. 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. 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.