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<p>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 <i>KDR</i>, <i>PLCG1</i>, and <i>POT1</i>. Meanwhile, cutaneous angiosarcomas are enriched for MYC-driven programs, UV mutational signatures, immune checkpoint gene expression, and <i>TP53</i>, <i>FLT4</i>, and <i>BRAF</i> mutations. Germline <i>POT1</i> 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, <i>POT1</i>-mutated tumors underexpress <i>TERT</i> and overexpress <i>CHAMP1</i>. Altogether, these findings elucidate the molecular framework of angiosarcoma, nominate therapeutic targets, and highlight the power of direct patient engagement in rare cancers.</p>

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Patient-partnered multiomics reveals the molecular architecture of angiosarcoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月24日

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  • 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

摘要

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.