This observation supports a recent model of sarcomagenesis in which osteochondroma cells bear EXT homozygous inactivation, whereas chondrosarcoma-initiating cells are EXT-expressing cells.
By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas.
Malignant transformation was observed in 5% of patients, and no evidence of association between chondrosarcoma onset and EXT mutation, sex, severity of disease, or number of lesions was detected.
Immunohistochemistry was used to assess HSPG (CD44v3 and SDC2), WNT (beta-catenin), and TGF-beta (PAI-1 and phosphorylated Smad2) signaling, whereas IHH signaling was studied both by quantitative polymerase chain reaction and in vitro. mRNA levels of both EXT1 and EXT2 were normal in central chondrosarcomas; genomic alterations were absent in these regions and in 30 other HSPG-related genes.
When considering tumor development in primary chondrosarcoma, we should include mutations in EXT2, along with the status of other members of the EXT gene family.
Mutations of EXT1 and EXT2 have rarely been detected in sporadic secondary chondrosarcomas from osteochondroma; these frequently display loss of heterozygosity at the EXT1 and EXT2 loci, but primary chondrosarcomas typically do not.
Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas.
Cellular factors that affect virus growth and replication are often key regulators of the cell cycle and EXT1 is no different-humans with inherited mutations in EXT1 have developmental defects that lead to bone tumours (hereditary multiple exostoses, HME) and sometimes chondrosarcomas.
The EXT genes are a group of putative tumor suppressor genes that previously have been shown to participate in the development of hereditary multiple exostoses (HME), HME-associated and isolated chondrosarcomas.
Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies.
The complexity of the chromosome aberrations reflect the advanced stage of this chondrosarcoma; we suggest a possible involvement of the EXT1 gene located on chromosome 8.
These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma.
However, recent studies in sporadic and exostosis-derived chondrosarcomas suggest that the 8q24.1-encoded EXT1 gene may have tumour suppressor function.