USP6 – Aneurysmal Bone Cyst

This summary reviews multiple lines of evidence that establish a strong association between USP6 (HGNC:12629) and aneurysmal bone cyst (MONDO_0018815). Several independent case reports have documented USP6 gene rearrangements in aneurysmal bone cysts, with recurrent gene fusions involving different partner genes such as LUM, AHNAK, and FGFR1. These studies consistently identify USP6 rearrangements as a key diagnostic hallmark in affected patients (PMID:32859633, PMID:35717456, PMID:36356178).

The genetic evidence is robust, relying on diagnostic techniques including fluorescence in situ hybridization (FISH) and RNA sequencing. In multiple reports, these methodologies confirmed the presence of USP6 gene rearrangements in distinct cases and cohorts, affirming their reproducibility and diagnostic utility (PMID:35518535, PMID:38429095). Even though no coding point mutation in USP6 is documented in these studies, the observed fusion events serve as the molecular substrate for pathogenesis.

Functional assessments further substantiate the role of USP6 in aneurysmal bone cyst. Experimental studies demonstrate that gene fusion events result in promoter swapping, leading to USP6 overexpression and aberrant signaling that drives cyst formation. Although direct in vivo models of ABC are not yet fully developed, the available functional data align well with the molecular findings, reinforcing the mechanistic contribution of USP6 rearrangements to the disease (PMID:10882134).

There is no significant conflicting evidence to weaken this association. On the contrary, multi‐patient studies have reinforced that USP6 rearrangements are specific to primary aneurysmal bone cysts and can differentiate these lesions from histologically similar entities such as myositis ossificans or brown tumor (PMID:18265974).

The integration of genetic, experimental, and clinicopathologic data conclusively supports a strong association between USP6 rearrangements and aneurysmal bone cyst. This integrated appraisal emphasizes the diagnostic value of detecting USP6 gene fusions, which can guide therapeutic decisions and patient management in clinical practice.

Key take‑home sentence: Recurrent USP6 gene rearrangements are a robust molecular marker for aneurysmal bone cyst, providing critical support for precise diagnosis and effective clinical decision‑making.

References

• Cancer genomics & proteomics • 2020 • Fusion of the Lumican (LUM) Gene With the Ubiquitin Specific Peptidase 6 (USP6) Gene in an Aneurysmal Bone Cyst Carrying a t(12;17)(q21;p13) Chromosome Translocation PMID:32859633
• Virchows Archiv : an international journal of pathology • 2022 • Synchronous polyostotic solid variant of aneurysmal bone cyst involving thoracic vertebrae and harboring a novel AHNAK::USP6 gene fusion. A case report and review PMID:35717456
• Ophthalmic plastic and reconstructive surgery • 2023 • Aneurysmal Bone Cyst of the Orbit With USP6 Gene Rearrangement PMID:36356178
• Cureus • 2022 • A 5-Year-Old Female With an Aneurysmal Bone Cyst of the Proximal Humerus PMID:35518535
• Skeletal radiology • 2008 • Frequency of USP6 rearrangements in myositis ossificans, brown tumor, and cherubism: molecular cytogenetic evidence that a subset of "myositis ossificans-like lesions" are the early phases in the formation of soft-tissue aneurysmal bone cyst PMID:18265974
• Journal of clinical pathology • 2024 • Novel and unusual USP6 fusion partners in aneurysmal bone cyst and their role in pathogenesis and histopathological evaluation of this disease PMID:38429095
• Molecular cell • 2000 • The yeast hnRNP-like protein Hrp1/Nab4 marks a transcript for nonsense-mediated mRNA decay PMID:10882134

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