Angiosarcomas (ASs) are rare malignant vascular entities that can affect several regions in our body, including the heart. Cardiac ASs comprise 25–40% of cardiac sarcomas and can cause death within months of diagnosis. Thus, our aim was to identify potential differences and/or similarities between cardiac and extra-cardiac ASs to enhance targeted therapies and, consequently, patients’ prognosis. Whole-transcriptome analysis of three cardiac and eleven extra-cardiac non-cutaneous samples was performed to investigate differential gene expression and mutational events between the two groups. The gene signature of cardiac and extra-cardiac non-cutaneous ASs was also compared to that of cutaneous angiosarcomas (n = 9). H/N/K-RAS and TP53 alterations were more recurrent in extra-cardiac ASs, while POTE-gene family overexpression was peculiar to cardiac ASs. Additionally, in vitro functional analyses showed that POTEH upregulation conferred a growth advantage to recipient cells, partly supporting the cardiac AS aggressive phenotype and patients’ scarce survival rate. These features should be considered when investigating alternative treatments.
