Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities inEXT1orEXT2: homozygous deletion ofEXT1characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations inEXT1orEXT2combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation ofEXTand wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role ofEXTin their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions ofEXT1orEXT2are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation ofEXT1is found in ˜ 80% of our cases. FISH with anEXT1probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of theEXT1locus. By immunohistochemistry, we confirm the presence of cells with dysfunctionalEXT1in sporadic osteochondromas and show cells with functionalEXT1in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functionalEXTare predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating thatEXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.
Oncogene (2012) 31, 1095–1104; doi:10.1038/onc.2011.311; published online 1 August 2011