Clinical and Pathologic Description of Three Aneurysmal Bone Cyst Cases With Novel USP6 Fusion Partners Including SEC24D, HNRNPC, and ERRFI1

Abstract

Ubiquitin-specific protease 6 (USP6)-associated neoplasms constitute a spectrum of related entities that share clinical and morphological characteristics. They are defined molecularly by the presence of a USP6 gene rearrangement that results in promoter swap fusions involving a range of partner genes that activate expression of full-length USP6. In this study, we retrospectively reviewed whole transcriptome results and identified USP6-associated neoplasms in the St. Jude clinical genomics cohort, with a focus on novel fusion partners. Three patients (ages 4–21 years) presented with bone lesions affecting the humerus, femur, and distal femur, respectively. Histological examination revealed characteristic aneurysmal bone cyst (ABC) features including cystic spaces, osteoclastic giant cells with smooth muscle actin positivity in myofibroblastic cells, and at least one case with prominent myxoid features. Clinical whole transcriptome RNA sequencing identified three previously unreported USP6 fusions including SEC24D::USP6, HNRNPC::USP6, and ERRFI1::USP6. All fusions resulted in transcriptional upregulation of USP6. In this report, we summarize the clinical, radiographic, and histologic presentations of these new cases and describe the associated fusion structures.