EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Leiden University, Leyden, South Holland, Netherlands
The American Journal of Human Genetics (Impact Factor: 10.93). 10/1999; 65(3):689-98. DOI: 10.1086/302532
Source: PubMed


Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

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    • "Due to the dominant inheritance of the disease, two models, haploinsufficiency and lossof-heterozygosity (LOH), have been discussed as the molecular cause of MO. First studies analyzing tissue samples of MO patients detected loss of the wild type allele only in a subset of osteochondromas and the remaining, apparently heterozygous cases, led to ongoing discussions about haploinsufficiency as cause of MO (Bovee et al., 1999; Legeai-Mallet et al., 2000; Hall et al., 2002). A more recent study showed second hits in 63% of analyzed osteochondromas and revealed a mixture of HS positive and negative cells in the cartilage caps. "
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    • "Approximately 10% of patients have a de novo mutation10. Loss of the wild-type allele in hereditary cases indicates that inactivation of both EXT alleles is required for osteochondroma formation11, confirming their tumour suppressor action that results in a loss of chondrocyte polarization12. However, the inactivation of both alleles probably occurs only in some of the cells in the cartilaginous cap of osteochondromas1213. "
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