EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas

Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximat ely 15% of all chondrosarcomas arise within the cartilaginous cap of an ost eochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2 , located on 8q24 and 11p11-p12, respectively, have been cloned. It is stil l unclear whether osteochondroma is a developmental disorder or a true neop lasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteoch ondroma development, or whether a single EXT germline mutation acts in a do minant negative way. We therefore studied loss of heterozygosity and DNA pl oidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-m utation analysis was performed in a total of 34 sporadic and hereditary ost eochondromas and secondary peripheral chondrosarcomas. We demonstrated oste ochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 ost eochondromas. Furthermore, LOH was almost exclusively found at the EXT1 loc us in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations w ere detected in exon I of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-t ype allele in three osteochondromas, indicating that, in cartilaginous cell s of the growth plate, inactivation of both copies of the EXT1 gene is requ ired for osteochondroma formation in hereditary cases. In contrast, no soma tic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutati ons were found in the EXT2 gene.