A morphomolecular study of 175 ‘ USP6 ‐associated neoplasms’: The USP6 fusion partner strongly depends on morphology and location

Context Nodular fasciitis (NF), myositis ossificans/fibro‐osseous pseudotumor of the digits (MO/FP) and aneurysmal bone cyst (ABC) are grouped under the category of ‘ USP6 ‐associated neoplasms’ (UANs) due to their shared characteristic of an underlying USP6 rearrangement. Objective Our aim in this study is to investigate the diversity of USP6 rearrangements in UANs. Design We performed a clinicopathological and molecular investigation using targeted RNA sequencing on 124 cases of NF, 19 cases of MO/PF and 32 cases of ABC. Additionally, NF cases were scored for the presence of typical morphological features to assess their correlation with the detected USP6 fusion partner. Results In 85.4% of NF cases (88/103), we identified a USP6 rearrangement, with 46.6% exhibiting the classic MYH9::USP6 fusion and 53.4% displaying non‐ MYH9::USP6 fusions. Notably, classic histological features of NF strongly correlated with the presence of the MYH9::USP6 fusion, while specific NF locations (e.g. intramuscular, intra‐articular and intradermal) were significantly associated with non‐ MYH9 fusions. This study identified 22 novel USP6 fusion partners, demonstrating the fusion diversity within UANs. Additionally, there was minimal overlap in USP6 fusion partners between different UAN types. Conclusions A significant entity‐ and location‐specific USP6 fusion partner diversity was revealed among the UAN members. This supports the hypothesis that this diversity may be linked to the cell of origin. Additionally, molecular analysis can be valuable in diagnosing non‐classical NF.