Molecular Genetics of Multiple Osteochondromas

Abstract

Multiple osteochondromas (MOs) is an autosomal dominant disease characterised by MOs (previously named exostoses). Their formation requires bi‐allelic inactivation of EXT1 or EXT2 genes in growth plate cartilage. They encode glycosyltransferases that catalyse the chain elongation step in heparan sulfate biosynthesis and when mutated cause a variety of growth factor signalling defects, impaired cell–matrix interactions and loss of polarity. Osteochondromas are not clonal neoplasms, but a mixed population of cells harbouring homozygous loss of either EXT genes or cells retaining the EXT wild‐type allele. About 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary chondrosarcoma. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation, possibly by inactivation of the CDKN2A locus. This locus encodes INK4a (p16), which regulates RB1, and p19ARF, which regulates P53. Inactivation of CDKN2A by mutation or deletion is a common pathway for oncogenesis.

Key Concepts

  • Patients with MO are characterised genetically by germline mutations in EXT1 and EXT2 genes and phenotypically by the development of at least two osteochondromas.
  • Osteochondroma is a benign cartilage‐capped bony projection arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone.
  • Osteochondromas are the most frequent cartilaginous lesions, most often found on the femur (21%), humerus (17%) and tibia (11%).
  • Somatic inactivation of both EXT alleles results in significantly shorter heparan sulfate chains.
  • Defective heparan sulfate biosynthesis results in abnormal diffusion and signalling of IHH and FGFR3 causing increased proliferation and delayed differentiation.
  • Approximately 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary peripheral chondrosarcoma.
  • An osteochondroma cap exceeding 1.5–2 cm in adults is suggestive of malignancy.
  • The most common location for malignant transformation of an osteochondroma is the pelvis, where large lesions can be difficult to excise completely.
  • Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation.
  • Secondary peripheral chondrosarcoma typically shows chromosome instability with gains and losses and genomic diversity that increases with increasing grade of malignancy. Loss of heterozygosity for the chromosomal bands bearing the RB1 and CDKN2A (p16INK4a) tumour suppressor genes is often found.

Keywords: EXT; CDKN2A; heparan sulfate; osteochondroma; chondrosarcoma; cartilage tumours; bone neoplasm

Figure 1. (a) Gross specimen of an osteochondroma. The lesion consists of a stalk of medullary bone covered by a smooth, pale, blue‐grey cartilage cap. (b) Osteochondroma is composed of three distinct layers: perichondrium, cartilage cap and bone. The cartilage cap shows a growth plate–like columnar arrangement of chondrocytes. Endochondral ossification is seen at the cartilage bone interface. Cellularity is variable. Binucleated cells, calcification, necrosis, nodularity and cystic changes can be seen.
Figure 3. (a) Gross specimen of a chondrosarcoma arising in the cartilaginous cap of an osteochondroma. Large lobules of tumour cartilage separated by fibrous tissue are seen invading soft tissue. (b) Lobules of chondroid matrix with closely arranged cells in lacunae. The neoplasm contains highly cellular areas with spindle cell change, indicating high‐grade chondrosarcoma.
Figure 2. Schematic representation of changes in morphology and expression of signalling pathways during malignant transformation of an osteochondroma in patients with MO. Different tumour grades are represented by their histology. Progression towards secondary peripheral chondrosarcoma is characterised by a decrease in chondroid matrix and an increase in cellularity and cellular disorganisation. Clonal cell selection occurs during the formation of a secondary peripheral chondrosarcoma. Homozygous EXT‐mutated cells (EXT−/−; green cells) and heterozygous EXT‐mutated cells (EXT+/−; blue cells) compose the multiple osteochondroma cap. Preferentially, the heterozygous EXT‐mutated cells acquire extra genetic alteration(s) to give rise to a secondary peripheral chondrosarcoma, that is by inactivation of the CDKN2A locus. The chondrosarcoma cells (red cells) get a proliferative advantage, overgrowing the osteochondroma cells. During malignant transformation/progression, PTHLH, TGF‐β and FGF signalling increase. Similar increase is seen for EXT1 and heparan sulfate. In addition, IHH and Wnt signalling decrease. (Bovée et al., ); (Hameetman et al., , Reijnders et al., ); (de Andrea et al., )
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Further Reading

de Andrea CE and Hogendoorn PCW (2014) Molecular genetics of chondroid tumours. Diagnostic Histopathology 20: 165–171.

Busse‐Wicher M, Wicher KB and Kusche‐Gullberg M (2014) The exostosin family: proteins with many functions. Matrix Biology 35: 25–33.

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Pansuriya TC, Kroon HM and Bovée JVMG (2010) Enchondromatosis: insights on the different subtypes. International Journal of Clinical and Experimental Pathology 3: 557–569.

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de Andrea, Carlos E, Hogendoorn, Pancras CW, and Bovée, Judith VMG(Jan 2016) Molecular Genetics of Multiple Osteochondromas. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024327]