GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328026/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328026GEOGSEfalseMiT Fusions, TSC1–TSC2 Divergence, and Stem-like Programs Reveal Distinct Origins and Vulnerabilities in PEComa [RNA-seq]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.2026/04/18GSE328026GSM9670529GSM9670528GSM9670527GSM9670526GSM9670525GSM9670524GSM9670534GSM9670533GSM9670499GSM9670532GSM9670531GSM9670498GSM9670530GSM9670497GSM9670496GSM9670495GSM9670494GSM9670493GSM9670492GSM9670491GSM9670490GSM9670539GSM9670538GSM9670537GSM9670536GSM9670535GSM9670545GSM9670501GSM9670500GSM9670544GSM9670543GSM9670542GSM9670541GSM9670540GSM9670509GSM9670508GSM9670507GSM9670506GSM9670505GSM9670549GSM9670548GSM9670504GSM9670503GSM9670547GSM9670502GSM9670546GSM9670512GSM9670511GSM9670555GSM9670510GSM9670554GSM9670553GSM9670552GSM9670551GSM9670550GSM9670519GSM9670518GSM9670517GSM9670516GSM9670515GSM9670514GSM9670513GSM9670523GSM9670522GSM9670489GSM9670488GSM9670521GSM9670520GSM96704872030130173328026Homo sapiens