© The Author 2007. Published by Oxford University Press.
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The Role of EXT1 in Nonhereditary Osteochondroma: Identification of Homozygous Deletions
Affiliations of authors: Departments of Pathology (LH, AY, AMCJ, JVMGB, PCWH), Molecular Cell Biology (KS, JK), and Orthopedic Surgery (AHMT), Leiden University Medical Center, Leiden, The Netherlands; Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (MVD, HVD)
Correspondence to: Pancras C. W. Hogendoorn, MD, PhD, Department of Pathology, Leiden University Medical Center, PO Box 9600 L1-Q, 2300 RC Leiden, The Netherlands (e-mail: p.c.w.hogendoorn{at}lumc.nl).
Background: Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However, 85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare, but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas.
Methods: Eight nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic hybridization (array-CGH) analysis for chromosome 8q. The array-CGH results were validated by subjecting tumor DNA to multiple ligation-dependent probe amplification (MLPA) analysis for EXT1. EXT1 locus–specific fluorescent in situ hybridization (FISH) was performed on nuclei isolated from the three tissue components of osteochondroma (cartilage cap, perichondrium, bony stalk) to examine which parts of the tumor are of clonal origin.
Results: Array-CGH analysis of tumor DNA revealed that all eight osteochondromas had a large deletion of 8q; five tumors had an additional small deletion of the other allele of 8q that contained the EXT1 gene. MLPA analysis of tumor DNA confirmed these findings and identified two additional deletions that were smaller than the limit of resolution of array-CGH. FISH analysis of the cartilage cap, perichondrium, and bony stalk showed that these homozygous EXT1 deletions were present only in the cartilage cap of osteochondroma.
Conclusion: EXT1 functions as a classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas.
| CONTEXT AND CAVEATS Prior knowledge Mutations in the EXT1 gene cause multiple osteochondromas, a rare hereditary disorder characterized by multiple benign bone tumors. However, it is not known whether the EXT1 gene is also involved in the more common solitary (nonhereditary) osteochondromas. Study design Molecular cytogenetic study of eight nonhereditary osteochondromas and the three tissue components (cartilage cap, perichondrium, and bony stalk) of one osteochondroma. Contribution Inactivation of both copies of EXT1, which is one of the hallmarks of a classical tumor suppressor gene, occurs in nonhereditary osteochondromas, specifically in the cartilage cap. Implications All osteochondromas, both hereditary and nonhereditary, are neoplastic and develop as a result of the complete loss of one of the EXT genes. Limitations Due to the rarity of osteochondromas, few tumor samples were examined, and only one yielded sufficient material for analysis of tissue components. LOH due to mitotic recombination without copy number alterations could not be detected by the techniques used.
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Manuscript received September 11, 2006; revised December 15, 2006; accepted January 19, 2007.
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J Natl Cancer Inst 2007 99: 337.
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