Patient-partnered multiomics reveals the molecular architecture of angiosarcoma
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.
Authors
- Hadley Grundman (ORCID: https://orcid.org/0000-0001-7222-6365)
- Lauren Sterlin
- Parker Chastain (ORCID: https://orcid.org/0000-0003-0220-3373)
- Mary McGillicuddy
- Erica Pimenta (ORCID: https://orcid.org/0000-0002-9684-6486)
- Hoyin Chu (ORCID: https://orcid.org/0000-0001-8630-3667)
- Marissa Hollyer
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Diane M. Diehl (ORCID: https://orcid.org/0009-0001-8965-8874)
- Jorge Gómez Tejeda Zañudo (ORCID: https://orcid.org/0000-0002-1092-0068)
- Beena Thomas
- Corrie Painter (ORCID: https://orcid.org/0000-0001-6174-1548)
- Hani Choudhry (ORCID: https://orcid.org/0000-0003-0401-6619)
- Caleb A. Lareau (ORCID: https://orcid.org/0000-0003-4179-4807)
- Christopher R. Reilly (ORCID: https://orcid.org/0000-0002-9551-7533)
- Oyin Alao
- Elana Anastasio
- Jillian Gutierrez
- Nikhil Wagle (ORCID: https://orcid.org/0000-0003-3332-9438)
- Ilan K. Small
- Jeremy Johnson (ORCID: https://orcid.org/0000-0001-8548-5972)
- Jason L. Hornick (ORCID: https://orcid.org/0000-0001-6475-8345)
- Nouf Alharbi (ORCID: https://orcid.org/0000-0002-1720-5606)
- Saud H. AlDubayan (ORCID: https://orcid.org/0000-0001-9062-3399)
- Brittany A. Borden
- Seunghun Han (ORCID: https://orcid.org/0000-0002-0235-7252)
- Priyanka Bhakhri
- Kolbe Phelps
- Delia Sosa
- Riaz Gillani
- Matthew Nagy (ORCID: https://orcid.org/0000-0001-5087-6674)
- Sabrina Y. Camp
- Will Terzi
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- King Abdulaziz University (SA)
- King Saud bin Abdulaziz University for Health Sciences (SA)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-24
- DOI
- https://doi.org/10.1038/s41467-026-75810-2
- Primary Topic
- Vascular Tumors and Angiosarcomas
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Rally Foundation
- American Society of Clinical Oncology
- Edward P. Evans Foundation
- National Institutes of Health
- National Cancer Institute
- DOD Peer Reviewed Cancer Research Program