EXT1 – Chondrosarcoma

Chondrosarcoma is a malignant cartilage‐forming tumor, approximately 15% of which arise within the cartilaginous cap of an osteochondroma. The EXT1 gene encodes a glycosyltransferase critical for heparan sulfate biosynthesis and has been implicated as a tumor‐suppressor in hereditary multiple exostoses (HME) and secondary chondrosarcoma formation.

In an analysis of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas, osteochondroma was shown to be a true neoplasm, with aneuploidy observed in 4 of 10 lesions and loss of heterozygosity (LOH) at the EXT1 locus in 5 of 14 tumors (PMID:10441575).

Four novel constitutional EXT1 cDNA alterations in exon 1 were detected in 4 unrelated HME probands; in two families, a germline EXT1 mutation coupled with LOH in three separate osteochondromas supports a two‐hit tumor‐suppressor model (PMID:10441575).

No somatic EXT1 cDNA alterations were identified in sporadic osteochondromas, nor were any EXT2 mutations found in this cohort, underscoring the predominant role of EXT1 in osteochondroma‐associated chondrosarcoma (PMID:10441575).

Biallelic inactivation of EXT1 impairs heparan sulfate polymerization, disrupting chondrocyte proliferation control and facilitating malignant transformation in cartilage caps.

Together, these genetic and cytogenetic data establish EXT1 as a tumor suppressor in chondrosarcoma arising from osteochondroma, supporting germline testing and LOH analysis for risk stratification in HME patients.

Key take-home: EXT1 mutation and LOH analysis guide diagnostic and prognostic evaluation of chondrosarcoma risk in osteochondroma patients.

References

• American journal of human genetics • 1999 • EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. PMID:10441575

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