GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328029/primaryOK200Methylation profilingHomo sapiensMethylation profiling by genome tiling arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328029GEOGSEfalseMiT Fusions, TSC1–TSC2 Divergence, and Stem-like Programs Reveal Distinct Origins and Vulnerabilities in PEComa [Methylation]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.2026/04/18GSE328029GSM9670609GSM9670608GSM9670629GSM9670607GSM9670606GSM9670628GSM9670627GSM9670605GSM9670626GSM9670604GSM9670603GSM9670625GSM9670624GSM9670602GSM9670623GSM9670601GSM9670611GSM9670633GSM9670632GSM9670610GSM9670599GSM9670631GSM9670598GSM9670597GSM9670630GSM9670596GSM9670595GSM9670594GSM9670593GSM9670592GSM9670591GSM9670590GSM9670619GSM9670618GSM9670617GSM9670616GSM9670615GSM9670614GSM9670613GSM9670612GSM9670600GSM9670589GSM9670622GSM9670588GSM9670621GSM967062021145328029Homo sapiens