Multi-omics profiling identifies HMGA2 fusions as defining a distinct and prognostically favorable subtype of dedifferentiated liposarcoma with rhabdomyosarcomatous differentiation.

Dedifferentiated liposarcoma (DDLPS) with rhabdomyosarcomatous differentiation is associated with a poorer prognosis compared to other DDLPS subtypes. This highlights the importance of exploring its clinicopathological, immune microenvironment, and molecular characteristics to inform personalized treatment strategies. In this study, we investigated five DDLPS patients with rhabdomyosarcomatous differentiation, summarizing their clinicopathological features, immune landscape through immunohistochemistry, and molecular alterations via next-generation sequencing (NGS) analysis, including both DNA and RNA sequencing. Additionally, we conducted a comparative analysis between the well-differentiated (WD) and dedifferentiated (DD) components within these tumors. Our findings identified recurrent HMGA2 fusions, including HMGA2-C12orf74, HMGA2-LPP, HMGA2-BASP1, HMGA2-NAV3, HMGA2-MYF6, and MYO10-HMGA2, which were mutually exclusive with MYC amplification. Notably, these HMGA2 fusions were associated with a more favorable prognosis, demonstrating a mean relapse-free time of 24.0 months, compared to only 2 months in patients without the fusion (P = 0.039). Chromosomal alterations were frequently observed, with 12q amplification being the most prevalent across all 10 tumor samples (5 DD and 5 WD components). Furthermore, DD components exhibited significantly higher levels of copy number variations (CNVs) than their WD counterparts (P = 0.01), with 15q loss exclusively detected in DD components (P < 0.01). In terms of the immune microenvironment, both DD and WD components showed significant infiltration of T cells and M2 macrophages. However, CD20+ B cells were more abundant in WD components compared to DD components. Additionally, DD components harboring MYC amplification exhibited a more immunosuppressive state than those containing HMGA2 fusions, further underscoring the heterogeneity of these tumors. In conclusion, our multi-omics analysis identifies HMGA2 fusion as a promising diagnostic and prognostic biomarker for DDLPS with rhabdomyosarcomatous differentiation. The comprehensive molecular and immune landscape of this tumor subtype not only deepens our understanding of its pathophysiology but also provides critical insights for future precision medicine strategies.