Abstract
Renal angiomyolipoma (AML) encompasses benign variants (lipomatous [L-AML], myomatous [M-AML]) and epithelioid AML (eAML), a potentially malignant subtype associated with aggressive behavior. While TSC1/TSC2 mutations are frequent, the molecular drivers underlying eAML pathogenesis remain unclear. Whole-exome sequencing (WES) was performed on 35 AML samples (15 eAML, 10 L-AML, 10 M-AML) with matched germline controls. Driver genes were identified using OncodriveCLUST and MutSigCV. Validation was conducted on 71 FFPE samples integrating expression profiling and survival analysis. The finding suggested that TSC2 emerged as the most frequently mutated pathogenic gene in AML, exhibiting a mutation rate of 69 %. TSC2, POLDIP2, NEFH, and MUC2 emerged as potential driver genes across AML subtypes, whereas RHPN2, ASXL1, TOP3B, and USP35 showed subtype-specific mutations. Notably, distinct cytogenetic aberrations were observed among AML variants, including deletions at 3p26.3, 5p13.1, 6p22.1, and 11p11.11. Clonal evolution analysis suggested that l-AML and eAML, as well as M-AML and eAML, may originate from a common ancestral clone, retaining early mutations and acquiring additional alterations post-divergence. Low TSC2/POLDIP2 and high NEFH/MUC2 expression correlated with favorable survival in eAML patients. Importantly, lower TSC2/POLDIP2 expression also predicted superior response rates to Everolimus therapy. In conclusion, our study comprehensively delineates genomic distinctions and evolutionary trajectories among renal AML subtypes, establishing TSC2, POLDIP2, NEFH, and MUC2 as prognostic biomarkers and therapeutic predictors, facilitating precision medicine in eAML management.