Kinase Fusions Define a Distinct Subset of BRAF V600E‑Negative Metanephric Adenomas

Metanephric adenoma (MA) is a rare benign renal neoplasm characterized by recurrent BRAF V600E mutations in ∼80% to 90% of cases. The molecular drivers in BRAF V600E‑negative MAs remain poorly understood, although rare kinase fusions have been reported. Here, we present a multi‑institutional series of 7 BRAF V600E‑negative MAs with confirmed kinase fusions. The patients included 5 women and 2 men, with a median age of 43 years (range: 24 to 62 y). All tumors were uncapsulated and exhibited typical MA histology. Notably, leaf‑like structures formed by branching dilated tubules surrounding dense small acini were observed in 4 of 7 cases, and thyroid follicle‑like structures and/or microcystic/reticular patterns were observed in 3 of 7 cases. The majority of cases showed marked paucity of edematous or fibrous stroma. By immunohistochemistry, all cases were diffusely positive for WT1 and CD57, negative for BRAF V600E (clone VE1), and largely negative for CK7 and AMACR. Targeted RNA sequencing identified fusions involving RET (CCDC6::RET in 2 cases, ANKRD26::RET in 1), ALK (STRN::ALK in 2), ROS1 (RDX::ROS1 in 1), and BRAF (CUX1::BRAF in 1). All fusions preserved the kinase domain of the respective genes. Fluorescence in situ hybridization or reverse‑transcriptase PCR confirmed the rearrangements in available cases. In contrast, targeted RNA sequencing of 7 BRAF V600E‑mutant MAs revealed no kinase fusions. All patients underwent partial nephrectomy and remained disease‑free during follow‑up (median: 18 mo, range: 14 to 115 mo). Our findings demonstrate that kinase fusions, including RET, ALK, ROS1, and BRAF, represent alternative drivers in BRAF V600E‑negative MAs, expanding the molecular spectrum of MA. In VE1-negative cases with classic MA histology, targeted RNA sequencing for these fusions may serve as a useful diagnostic adjunct.