Patient-partnered multiomics reveals the molecular architecture of angiosarcoma

作者：Hoyin Chu, Marissa Hollyer, Brittany A. Borden, Christopher R. Reilly, Jorge Gómez Tejeda Zañudo, Beena Thomas, Kolbe Phelps, Erica Pimenta, Seunghun Han, Sabrina Y. Camp, Riaz Gillani, Jillian 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 Painter, Saud H. AlDubayan · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-75810-2 · 研究领域：Vascular Tumors and Angiosarcomas、Cardiac tumors and thrombi、Soft tissue tumors and treatment

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. A patient-partnered multi-omics study of 254 angiosarcoma patients reveals distinct molecular and transcriptional subtypes and a 92.7-fold elevated disease risk in germline POT1 pathogenic variant carriers.