SNOMEDCT: 1163016002, 443520009; ORPHA: 55880; DO: 3371;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.11 | Chondrosarcoma | 215300 | Somatic mutation | 3 | EXT1 | 608177 |
A number sign (#) is used with this entry because of evidence that chondrosarcoma may result from mutation, either constitutional or somatic, in the EXT1 gene (608177) on chromosome 8q24.
Hecht et al. (1997) reported a patient with only chondrosarcoma from a family with a history of multiple exostoses (see 133700).
Schajowicz and Bessone (1967) described 3 brothers who, respectively, developed chondrosarcoma of the pelvic bone at 18 years, of the fibula and femur at 16 years, and of the femur at 17 years. Two brothers and a sister were living and well. Karyotypes were normal. See osteogenic sarcoma (259500).
Linkage Studies
In a large multigenerational family with multiple exostoses and, in 1 member, a chondrosarcoma, Hecht et al. (1997) found linkage of the disease to chromosome 11 markers. Loss of marker D11S903 was observed in constitutional DNA from all affected individuals and in the tumor sample. In further studies of constitutional and chondrosarcoma DNA from 6 unrelated individuals, 2 of whom had multiple exostoses, 1 tumor from an individual with multiple exostoses showed LOH for chromosome 8 markers in the region where the EXT1 gene maps (8q24.1), and a person with a sporadic chondrosarcoma was found to have a tumor-specific LOH and a homozygous deletion of chromosome 11 markers from the pericentric region, where the EXT2 gene maps. These findings suggested to Hecht et al. (1995) that EXT genes may be tumor suppressor genes and that the initiation of tumor development may follow a multistep model.
Using LOH analysis of chondrosarcomas and chondroblastomas, Hecht et al. (1995) identified additional LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. The authors reported that a sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, whereas a second chondrosarcoma underwent LOH for EXT2 and chromosome 10.
In a patient (individual 6) with chondrosarcoma, Hecht et al. (1997) identified an EXT1 mutation in the constitutional DNA (608177.0005), but the tumor tissue had retained the wildtype allele.
Somatic Mutations
In a patient (individual 10) with somatic chondrosarcoma, Hecht et al. (1997) identified a mutation in the tumor tissue (608177.0006), which was not present in the constitutional DNA.
Tarpey et al. (2013) reported comprehensive genomic analyses of 49 individuals with chondrosarcoma and identified hypermutability of the major cartilage collagen gene COL2A1 (120140), with insertions, deletions, and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, Tarpey et al. (2013) identified mutations in IDH1 (147700) or IDH2 (147650) (59%), TP53 (191170) (20%), the RB1 pathway (see 614041) (33%), and Sonic hedgehog signaling (600725) (18%).
Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8. Am. J. Hum. Genet. 56: 1125-1131, 1995. [PubMed: 7726168]
Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am. J. Hum. Genet. 60: 80-86, 1997. [PubMed: 8981950]
Schajowicz, F., Bessone, J. E. Chondrosarcoma in 3 brothers: a pathological and genetic study. J. Bone Joint Surg. Am. 49: 129-141, 1967. [PubMed: 6015756]
Tarpey, P. S., Behjati, S., Cooke, S. L., Van Loo, P., Wedge, D. C., Pillay, N., Marshall, J., O'Meara, S., Davies, H., Nik-Zainal, S., Beare, D., Butler, A., and 22 others. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nature Genet. 45: 923-926, 2013. [PubMed: 23770606] [Full Text: https://doi.org/10.1038/ng.2668]