Hoyin Chu, Marissa Hollyer, Brittany A Borden, Christopher R Reilly, Jorge Gómez Tejeda Zañudo, Beena S Thomas, Kolbe Phelps, Erica Maria Pimenta, Seunghun Han, Sabrina Y Camp, Riaz Gillani, Jacob Gutierrez, Caleb A Lareau, Matthew Nagy, Jeremy Johnson, Oyin Alao, Hadley Grundman, Lauren Sterlin, Will Terzi, Delia Sosa, Ilan K Small, Mary McGillicuddy, Nouf Alharbi, Elana Anastasio, Parker Chastain, Priyanka Bhakhri, Jason L Hornick, Hani Choudhry, Diane M Diehl, Eliezer M Van Allen, Nikhil Wagle, Corrie A Painter, Saud AlDubayan
Angiosarcoma is a poorly understood sarcoma due to its high heterogeneity and rarity. Here we show a comprehensive clinical and molecular analysis of a large cohort of 254 angiosarcoma patients through the patient-partnered Angiosarcoma Project. By integrating transcriptomic, somatic, and germline variant data, we find that subcutaneous angiosarcomas frequently exhibit TGF-β and receptor tyrosine kinase signaling upregulation, with driver mutations in KDR, PLCG1, and POT1. Meanwhile, cutaneous angiosarcomas are enriched for MYC-driven programs, UV mutational signatures, immune checkpoint gene expression, and TP53, FLT4, and BRAF mutations. Germline POT1 pathogenic variant carriers have a 92.7-fold higher risk of developing angiosarcoma, with 'double-hit' germline and somatic variant carriers developing disease decades earlier. Additionally, POT1-mutated tumors underexpress TERT and overexpress CHAMP1. Altogether, these findings elucidate the molecular framework of angiosarcoma, nominate therapeutic targets, and highlight the power of direct patient engagement in rare cancers.