Genomic and Transcriptomic Characterization of Angiosarcomas: Focus on Cardiac Origin

Cardiac angiosarcoma is a rare and aggressive malignancy with limited therapeutic options, and its molecular features remain poorly defined. This study sought to characterize the genomic and transcriptomic landscape of cardiac angiosarcoma and to explore molecular features associated with clinical outcomes, chemotherapy response, and potential therapeutic vulnerabilities. We retrospectively analyzed 35 patients with cardiac angiosarcoma who underwent whole-exome sequencing (n = 11) and/or whole-transcriptome sequencing (n = 33). An additional 35 patients with angiosarcoma from noncardiac or unknown primary sites were included for comparative genomic analyses. Cardiac angiosarcoma frequently harbored alterations in KDR (55%), PLCG1 (45%), and CCND1 (36%), with recurrent amplifications at 8p23.1, 8p23.2, and 4q12 and recurrent deletions at 17q21.31, 15q13.2, 8p23.1, and 2q11.2. Transcriptomic analyses identified differential expression patterns associated with relapse, mortality, and chemotherapy response. Tumors from the low-relapse-risk group were enriched for axon guidance, whereas those from the high-relapse-risk group were enriched for cytokine-cytokine receptor interaction. Approximately one-third of patients exhibited high infiltration of most immune cell populations. Potentially actionable genomic alterations were identified in 71.7% of angiosarcomas. Compared with noncardiac angiosarcomas, cardiac tumors showed higher frequencies of KDR, CCND1, MCL1, and PLCG1 alterations and unique enrichment of the apelin signaling and vascular smooth muscle contraction pathways. Genomic and transcriptomic profiling of cardiac angiosarcoma revealed a distinct molecular landscape with candidate prognostic and therapeutic markers, providing a foundation for future precision oncology strategies in this rare disease.