Oliveira, André M.

Abstract Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically occurs during the first two decades of life. ABC was regarded historically as a nonneoplastic process, but recent cytogenetic data have shown clonal rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic basis in at least some ABCs. Herein we show that a recurring ABC chromosomal translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6 fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms. CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic mechanism in which deregulated USP6 transcription results from juxtaposition to the highly active CDH11 promoter.

Background: p45 S phase kinase-associated protein-2 (p45skp2), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCFskp2). The latter has been implicated in the ubiquitination and degradation of p27kip1 (p27) and G1-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated. Methods: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. Results: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (≥ 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P = .002) and Ki-67 proliferative index (r = 0.44; P < .0001), but not with p27 expression (r = −0.02; P = .80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival. Conclusion: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.