The Role of EXT1 in Nonhereditary Osteochondroma: Identification of Homozygous Deletions

Hameetman, Liesbeth; Szuhai, Károly; Yavas, Ayse; Knijnenburg, Jeroen; Duin, Mark van; Dekken, Herman van; Taminiau, A. H. M.; Cleton‐Jansen, Anne‐Marie; Bovée, Judith V.M.G.; Hogendoorn, Pancras C.W.

doi:10.1093/jnci/djk067

Cited by 105 publications

(93 citation statements)

References 38 publications

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“…Recent experimental studies using mice and zebrafish knockdown models show that homozygous inactivation of Ext1 or Ext2 is required for osteochondromagenesis (Cle´ment et al, 2008;Jones et al, 2010;Matsumoto et al, 2010). In humans, loss of the remaining wild-type allele of EXT has been detected in approximately 40% of sporadic and multiple osteochondromas (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010). In sporadic osteochondromas, we have described homozygous deletions of EXT1 in B80% of the cases (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010).…”

Section: Introductionmentioning

confidence: 81%

“…In some of these negative cases, somatic mosaicism with large genomic deletions of EXT1 and EXT2 have been described as the underlying mechanism of multiple osteochondroma formation (Szuhai et al, 2011). In sporadic osteochondromas, homozygous deletions of EXT1 are identified (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010;Szuhai et al, 2011). Recent experimental studies using mice and zebrafish knockdown models show that homozygous inactivation of Ext1 or Ext2 is required for osteochondromagenesis (Cle´ment et al, 2008;Jones et al, 2010;Matsumoto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…In humans, loss of the remaining wild-type allele of EXT has been detected in approximately 40% of sporadic and multiple osteochondromas (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010). In sporadic osteochondromas, we have described homozygous deletions of EXT1 in B80% of the cases (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010). It was shown recently that during the formation of osteochondromas, chondrocytes with functional EXT from the growth plate or the neighboring tissue are being integrated into the cartilaginous cap, generating a mosaic mixture of wild-type cells and cells with homozygous inactivation of EXT1 or EXT2 (de Andrea et al, , 2011Jones et al, 2010;Matsumoto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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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 in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are 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 of EXT1 is found in B80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. 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. 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 functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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“…Mutations in EXT1 (8q24.1) and EXT2 (11p11) genes are associated with osteochondromas [41][42][43][44]. EXT1 and EXT2 encode type II transmembrane glycosyltransferases [45,46], whose functions are not fully known.…”

Section: Osteochondromagenesismentioning

confidence: 99%

“…In some of these negative cases, somatic mosaicism with large genomic deletions of EXT1 and EXT2 has been described as the underlying mechanism of multiple osteochondromas formation [58]. In sporadic osteochondromas, homozygous deletions of EXT1 are often identified [42].…”

Section: Osteochondromagenesismentioning

confidence: 99%

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Andrea¹,

Hogendoorn²

2011

The Journal of Pathology

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Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM).Chondrocyte-matrix interactions compensate the lack of cell-cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short-and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell-matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild-type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the micro-environment is the site of the initiating processes that ultimately lead to cancer.

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Molecular Genetics of Multiple Osteochondromas

Andrea

Hogendoorn

Bovée

2016

Encyclopedia of Life Sciences

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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.

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The Role of EXT1 in Nonhereditary Osteochondroma: Identification of Homozygous Deletions

Abstract: EXT1 functions as a classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas.

Cited by 105 publications

References 38 publications

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Molecular Genetics of Multiple Osteochondromas

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