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Journal of Clinical Oncology, Vol 24, No 1 (January 1), 2006: pp. e1 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.4818
Aneurysmal Bone Cyst: A Neoplasm Driven by Upregulation of the USP6 OncogeneDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA
Department of Pathology, Children’s Hospital, Boston, MA
Department of Pathology, Massachusetts General Hospital, Boston, MA To the Editor: We wish to comment on an article by Mankin et al,1 published in the September 20, 2005, issue of the Journal of Clinical Oncology. The study describes their exceptional surgical experience with 150 patients diagnosed with aneurysmal bone cyst (ABC), and provides an updated surgical perspective of these tumors. However, the report overlooked important recent data on the biology and molecular genetics of these tumors. Primary ABC is an intriguing bone tumor that has characteristic clinical and pathologic findings. It has been widely regarded as a reactive process since its initial description in 1942 by Jaffe and Lichtenstein.2 Many different theories have been proposed for the pathogenesis of ABC and one of the most widely accepted was that a local circulatory abnormality led to increased venous pressure and resultant dilation of the local vascular network. The reactive nature of ABC was also supported by the fact that ABC-like areas can be seen in a variety of benign and malignant bone neoplasms, especially in association with giant cell tumor of the bone, chondroblastoma, and osteoblastoma. The reactive nature of ABC was initially challenged by the work of Panoutsakopoulos et al,3 who demonstrated that some primary ABCs exhibited the chromosomal translocation t(16;17)(q22;p13) as a recurrent cytogenetic abnormality. These initial observations by Panoutsakopoulos et al were later confirmed by Dal Cin et al.4 We extended these studies by showing that the t(16;17)(q22;p13) fuses the promoter region of the osteoblast cadherin 11 gene (CDH11) on chromosome 16q22 to the entire coding sequence of the ubiquitin protease USP6 gene (also known as TRE2 or TRE17) on chromosome 17p13, suggesting that the pathogenesis of most primary ABCs involves upregulation of USP6 transcription driven by the highly active CDH11 promoter.5 In a subsequent study of 52 primary ABCs, we found rearrangements of CDH11 and/or USP6 in almost 70% of the cases.6 Rearrangements of these genes were restricted to the spindle cells in the walls of ABC and were not found in multinucleated giant cells, inflammatory cells, endothelial cells, or osteoblasts.6 CDH11 and USP6 rearrangements were also investigated in 17 secondary ABCs but with negative results, which indicated that secondary ABCs seem to represent a nonspecific morphologic pattern in a diverse group of neoplasms. Furthermore, we have not found any association between CDH11 and USP6 rearrangements and several clinicopathologic variables, including recurrence-free survival.6 In a more recent publication, we cloned four novel ABC chromosomal translocations in which genes highly expressed in the mesenchymal/osteoblast context were fused to USP6, including TRAP150 (thyroid receptor-associated protein 150), ZNF9 (Zn Finger 9), OMD (OsteoMoDulin), and COL1A1 (Collagen 1A1).7 It is still uncertain how USP6 transcriptional upregulation drives ABC pathogenesis but recent work reveals that the USP6 gene product regulates actin remodeling and vesicular trafficking and may thus regulate cell motility and invasiveness.8,9 All of these studies have substantially contributed to our understanding of the pathogenesis of ABC, including its characterization as a clonal neoplastic disorder, the discovery of USP6 as its major oncogene, and the identification of the ABC neoplastic cell. The major challenges we all face now are not only to further understand the biology of USP6 and its mechanism in the pathogenesis of ABC but also how to translate this substantial new knowledge into better patient care. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Mankin HJ, Hornicek FJ, Ortiz-Cruz E, et al: Aneurysmal bone cyst: A review of 150 patients. J Clin Oncol 23:6756-6762, 2005 2. Jaffe H, Lichtenstein L: Solitary unicameral bone cyst: With emphasis on the roentgen picture, the pathologic appearance and the pathogenesis. Arch Surg 44:1004-1025, 1942 3. Panoutsakopoulos G, Pandis N, Kyriazoglou I, et al: Recurrent t(16;17)(q22;p13) in aneurysmal bone cysts. Genes Chromosomes Cancer 26:265-266, 1999[CrossRef][Medline] 4. Dal Cin P, Kozakewich HP, Goumnerova L, et al: Variant translocations involving 16q22 and 17p13 in solid variant and extraosseous forms of aneurysmal bone cyst. Genes Chromosomes Cancer 28:233-234, 2000[CrossRef][Medline] 5. Oliveira AM, Hsi BL, Weremowicz S, et al: USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res 64:1920-1923, 2004 6. Oliveira AM, Perez-Atayde AR, Inwards CY, et al: USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol 165:1773-1780, 2004 7. Oliveira AM, Perez-Atayde AR, Dal CP, et al: Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene 24:3419-3426, 2005[CrossRef][Medline] 8. Martinu L, Masuda-Robens JM, Robertson SE, et al: The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6. Mol Cell Biol 24:9752-9762, 2004 9. Masuda-Robens JM, Kutney SN, Qi H, et al: The TRE17 oncogene encodes a component of a novel effector pathway for Rho GTPases Cdc42 and Rac1 and stimulates actin remodeling. Mol Cell Biol 23:2151-2161, 2003
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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