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<p>Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent <i>MITF</i> rearrangements involving actin gene partners (<i>ACTA2</i>, <i>ACTG1</i> and <i>ACTB</i>). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for <i>TFE3</i>/<i>MITF</i> rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs—melanocytic, mesenchymal, or adipogenic—as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for <i>TP53</i>/<i>RB1</i> mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.</p>

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MiT fusions, TSC1–TSC2 divergence, and stem-like programs reveal distinct origins and vulnerabilities in PEComa

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Justine Gantzer,
  • Xiaofan Lu,
  • Céline Charon-Barra,
  • Charles Vinson,
  • Noëlle Weingertner,
  • Antonin Fattori,
  • Marie-Pierre Chenard,
  • Damien Plassard,
  • Serge Vicaire,
  • François Le Loarer,
  • Maud Toulmonde,
  • Marie Karanian,
  • Mehdi Brahmi,
  • Carine Ngo,
  • Axel Le Cesne,
  • Alice Hervieu,
  • Lenaïg Mescam-Mancini,
  • François Bertucci,
  • Juliette Beaujot,
  • Thomas Ryckewaert,
  • Philippe Rochaix,
  • Thibaud Valentin,
  • Nicolas Macagno,
  • Florence Duffaud,
  • Matthias Tallegas,
  • Bruno Chetaille,
  • Isabelle Valo,
  • Emmanuelle Bompas,
  • Marick Lae,
  • Flore Delalande,
  • Francisco Llamas-Gutierrez,
  • Nathalie Rioux-Leclercq,
  • Jean-Yves Blay,
  • Jean-Emmanuel Kurtz,
  • Gabriel G. Malouf

摘要

Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent MITF rearrangements involving actin gene partners (ACTA2, ACTG1 and ACTB). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for TFE3/MITF rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs—melanocytic, mesenchymal, or adipogenic—as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for TP53/RB1 mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.