MiT fusions, TSC1–TSC2 divergence, and stem-like programs reveal distinct origins and vulnerabilities in PEComa
Abstract
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.
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BibTeX
@article{gantzer2026fusions,
title = {{MiT fusions, TSC1–TSC2 divergence, and stem-like programs reveal distinct origins and vulnerabilities in PEComa}},
author = {Justine Gantzer and Xiaofan Lu and Céline Charon-Barra and Charles Vinson and Noëlle Weingertner and Antonin Fattori and Marie-Pierre Chenard and Damien Plassard and Serge Vicaire and François Le Loarer and Maud Toulmonde and Marie Karanian and Mehdi Brahmi and Carine Ngo and Axel Le Cesne and Alice Hervieu and Lenaig Mescam-Mancini and François Bertucci and Juliette Beaujot and Thomas Ryckewaert and Philippe Rochaix and Thibaud Valentin and Nicolas Macagno and Florence Duffaud and Matthias Tallegas and Bruno Chetaille and Isabelle Valo and Emmanuelle Bompas and Marick Laé and Flore Delalande and Francisco Llamas Gutierrez and Nathalie Rioux-Leclercq and Jean-Yves Blay and Jean-Emmanuel Kurtz and Gabriel G. Malouf},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-74545-4},
url = {https://hal.science/hal-05675887v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - MiT fusions, TSC1–TSC2 divergence, and stem-like programs reveal distinct origins and vulnerabilities in PEComa
AU - Justine Gantzer
AU - Xiaofan Lu
AU - Céline Charon-Barra
AU - Charles Vinson
AU - Noëlle Weingertner
AU - Antonin Fattori
AU - Marie-Pierre Chenard
AU - Damien Plassard
AU - Serge Vicaire
AU - François Le Loarer
AU - Maud Toulmonde
AU - Marie Karanian
AU - Mehdi Brahmi
AU - Carine Ngo
AU - Axel Le Cesne
AU - Alice Hervieu
AU - Lenaig Mescam-Mancini
AU - François Bertucci
AU - Juliette Beaujot
AU - Thomas Ryckewaert
AU - Philippe Rochaix
AU - Thibaud Valentin
AU - Nicolas Macagno
AU - Florence Duffaud
AU - Matthias Tallegas
AU - Bruno Chetaille
AU - Isabelle Valo
AU - Emmanuelle Bompas
AU - Marick Laé
AU - Flore Delalande
AU - Francisco Llamas Gutierrez
AU - Nathalie Rioux-Leclercq
AU - Jean-Yves Blay
AU - Jean-Emmanuel Kurtz
AU - Gabriel G. Malouf
PY - 2026
DA - 2026/10/14
JO - Nature Communications
DO - 10.1038/s41467-026-74545-4
UR - https://hal.science/hal-05675887v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -