Pathology and genetics of tumors of soft tissue and bone

Osteochondroma is the most common benign bone tumor and usually occurs in the metaphyseal region of the long bones This tumor takes the form of a cartilage-capped bony outgrowth on the surface of the bone The vast majority (85%) of osteochondromas present as solitary, nonhereditary lesions Approximately 15% of osteochondromas occur as multiple lesions in the context of hereditary multiple osteochondromas (HMOs), a disorder that is inherited in an autosomal dominant manner Most lesions appear in children and adolescents as painless, slow-growing masses However, depending on the location of the osteochondroma, significant symptoms may occur as a result of complications such as fracture, bony deformity, mechanical joint problems and vascular or neurologic compromise Malignant transformation of osteochondromas can occur later in adulthood but rarely metastasize The treatment of choice for osteochondroma is surgical unless the skeleton is still immature Pathogenetic analysis showed that HMOs are caused by mutations in either of two genes: exostosis (multiple)-1 (EXT1), which is located on chromosome 8q2411-q2413 or exostosis (multiple)-2 (EXT2), which is located on chromosome 11p11-12 Recently, biallelic inactivation of the EXT1 locus was described in nonhereditary osteochondromas The EXT1 and EXT2 proteins function in the biosynthesis of heparin sulfate proteoglycans (HSPGs) which are multifunctional proteins involved in several growth signaling pathways in the normal epiphyseal growth plate Reduced EXT1 or EXT2 expression in osteochondromas is associated with disordered cellular distribution of HSPGs, resulting in defective endochondral ossification which is likely to be involved in the formation of osteochondromas Here the clinical, radiological, pathological and pathogenetic features and the treatment modalities of osteochondroma are reviewed

Osteochondromas: review of the clinical, radiological and pathological features.

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell sarcoma (malignant melanoma of soft parts).

Chondrosarcoma is a malignant cartilage-forming tumour of bone, of which distinct clinicopathological subtypes are known. Conventional chondrosarcoma is notorious for its locally aggressive behaviour as well as for its resistance to chemotherapy and radiotherapy; so far surgery is the only effective therapeutic option. During the past 10 years, substantial new insights have been gained about molecular cell biology, molecular cytogenetics, and immunopathology, leading to better understanding of chondrosarcoma development at the molecular level, which will ultimately lead to better clinical understanding and possibly to the development of targeted treatment.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(05)70282-5.pdf

Emerging pathways in the development of chondrosarcoma of bone and implications for targeted treatment

Multiple osteochondromas (MO) is an autosomal dominant skeletal disease characterized by the formation of multiple cartilage-capped bone tumors growing outward from the metaphyses of long tubular bones. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs have been shown to play a role in the diffusion of Ihh, thereby regulating chondrocyte proliferation and differentiation. EXT1 is located at 8q24.11-q24.13, and comprises 11 exons, whereas the 16 exon EXT2 is located at 11p12-p11. To date, an EXT1 or EXT2 mutation is detected in 70-95% of affected individuals. EXT1 mutations are detected in +/-65% of cases, versus +/-35% EXT2 mutations in MO patient cohorts. Inactivating mutations (nonsense, frame shift, and splice-site mutations) represent the majority of MO causing mutations (75-80%). In this article, the clinical aspects and molecular genetics of EXT1 and EXT2 are reviewed together with 895 variants in MO patients. An overview of the reported variants is provided by the online Multiple Osteochondromas Mutation Database (http://medgen.ua.ac.be/LOVD).

https://onlinelibrary.wiley.com/doi/pdf/10.1002/humu.21123

Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb).

The EXT family of putative tumor suppressor genes affect endochondral bone growth, and mutations in EXT1 and EXT2 genes cause the autosomal dominant disorder Hereditary Multiple Exostoses (HME). Loss of heterozygosity (LOH) of these genes plays a role in the development of exostoses and chondrosarcomas. In this study, we characterized EXT genes in 11 exostosis chondrocyte strains using LOH and mutational analyses. We also determined subcellular localization and quantitation of EXT1 and EXT2 proteins by immunocytochemistry using antibodies raised against unique peptide epitopes. In an isolated non-HME exostosis, we detected three genetic hits: deletion of one EXT1 gene, a net 21-bp deletion within the other EXT1 gene and a deletion in intron 1 causing loss of gene product. Diminished levels of EXT1 and EXT2 protein were found in 9 (82%) and 5 (45%) exostosis chondrocyte strains, respectively, and 4 (36%) were deficient in levels of both proteins. Although we found mutations in exostosis chondrocytes, mutational analysis alone did not predict all the observed decreases in EXT gene products in exostosis chondrocytes, suggesting additional genetic mutations. Moreover, exostosis chondrocytes exhibit an unusual cellular phenotype characterized by abnormal actin bundles in the cytoplasm. These results suggest that multiple mutational steps are involved in exostosis development and that EXT genes play a role in cell signaling related to chondrocyte cytoskeleton regulation. Cell Motil. Cytoskeleton 48:149–162, 2001. © 2001 Wiley-Liss, Inc.

Michael Lovett

Papers

Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes.