Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses

Mertens, Fredrik; Helm, Sverre; Mitelman, Felix; Mandahl, Nils; Rydholm, Anders; Kreicbergs, Andris; Willén, Helena; Jonsson, Kjell

doi:10.1002/gcc.2870090103

Cited by 64 publications

(34 citation statements)

References 23 publications

(20 reference statements)

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“…Osteochondromas often show normal cytogenetics with loss of heterozygosity (LOH) at the EXT1 and EXT2 loci as the most characteristic aberrations (Bovée et al, 1999). However, some cytogenetic alterations have been detected, suggesting a clonal neoplastic growth (Mertens et al, 1994). In contrast, osteosarcomas are often characterized by an array of sequential and well-orchestrated genetic changes, with complex and heterogeneous chromosomal abnormalities (Sandberg and Bridge, 2003).…”

Section: Discussionmentioning

confidence: 99%

Case Report Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings

Engel¹,

Nogueira-Barbosa²,

Brassesco³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Osteochondroma is a cartilage capped benign tumor developing mainly at the juxta-epiphyseal region of long bones. The rate of malignant transformation, mainly into chondrosarcoma, is estimated to be less than 1-3%. Transformation into osteosarcoma is very rare and has been reported only thirteen times. There is little information on 449 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 11 (1): 448-454 (2012) Osteosarcoma arising from osteochondroma treatment and outcome. We report the case of a secondary osteosarcoma arising in the left tibia of a 23-year-old male, 10 years after the initial diagnosis of osteochondroma and after two partial resections. Malignant transformation occurred at the stalk and not at the cartilage cap, as would normally be expected. Chromosome banding analysis revealed the karyotype: 46,XY, t(3;13)(q21;q34) [2]/46,XY [18]. Records from additional cases will help determine the parameters that define these rare secondary bone lesions.

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Section: Discussionmentioning

confidence: 99%

Case Report Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings

Engel¹,

Nogueira-Barbosa²,

Brassesco³

et al. 2012

Genet. Mol. Res.

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“…56 During malignant transformation additional genetic alterations are obtained, 5 probably causing defects in mitotic checkpoints leading to chromosomal instability which in turn may cause aneuploidy including near-haploidy. 60 In osteochondromas near-haploidy is absent 61,62 and near-haploidy can therefore be considered a progression marker toward a low-grade malignant phenotype. Our results suggest that further progression toward highgrade chondrosarcoma is characterized by polyploidization.…”

Section: Discussionmentioning

confidence: 99%

Near-Haploidy and Subsequent Polyploidization Characterize the Progression of Peripheral Chondrosarcoma

Bovée

Royen

Bardoel

et al. 2000

The American Journal of Pathology

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Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of osteochondroma (peripheral chondrosarcoma). We previously used DNA flow cytometry to demonstrate that near-haploidy is relatively frequent in peripheral chondrosarcomas. We performed fluorescence in situ hybridization (FISH) to interphase nuclei using centromeric probes, a genome wide loss of heterozygosity (LOH) analysis, and comparative genomic hybridization on five peripheral chondrosarcomas. We demonstrated near-haploidy in two low-grade tumors with only one copy and LOH of most chromosomes. Few chromosomes are disomic, with retention of heterozygosity and overrepresentation at comparative genomic hybridization. One tumor contains both a near-haploid clone with chromosomes in monosomic and disomic state, and an exactly duplicated clone. Two high-grade tumors clearly demonstrate polyploidization because most chromosomes show LOH and two copies at FISH, whereas few chromosomes have four copies with retention of heterozygosity. Using DNA from a relative, we demonstrate that chromosome loss is random regardless of parental origin. Using FISH on paraffin slides, we exclude near-haploidy to result from meiosis-like division in binucleated cells, characteristic for chondrosarcoma. In conclusion, our results indicate that near-haploidy characterizes the progression from osteochondroma toward low-grade chondrosarcoma. Moreover, further progression toward high-grade chondrosarcoma is characterized by polyploidization. Chondrosarcoma, the second most common primary malignant bone tumor after osteosarcoma, is a malignant cartilage-forming tumor occurring predominantly in adults. The majority of chondrosarcomas develops de novo and is located centrally within the medullary cavity (central chondrosarcoma). In contrast, ϳ15% arise within the cartilage cap of a long-standing osteochondroma (peripheral chondrosarcoma), mostly in patients suffering from the hereditary multiple exostoses syndrome. Hereditary multiple exostoses syndrome is a familial disorder with an autosomal dominant mode of inheritance.1-4 Malignant transformation is estimated to occur in 1 to 5% of osteochondromas.The development of peripheral chondrosarcoma results in genetic instability characterized by a high percentage of loss of heterozygosity (LOH) and a wide variation in DNA ploidy.5 LOH in peripheral chondrosarcoma most frequently involves the TP53 (80%), RB1 (71%), and EXT1 (65%) loci. 5 In contrast, peridiploidy and a low percentage of LOH in central tumors indicates that a different oncogenic molecular mechanism may be operative. 5 We have detected hypodiploidy, which is uncommon for human solid tumors, in 29% of peripheral chondrosarcomas and not in central chondrosarcomas.5 Others mention hypodiploidy in 8 to 31% of chondrosarcomas without further subclassification.6 -9 Near-haploidy, which is a very rare phenomenon in human solid tumors in general, is found especially in low-grade peripheral chon...

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“…However, later studies detected cytogenetic aberrations suggesting that loss or mutation of EXT1 and EXT2 are important in the pathogenesis of sporadic as well as hereditary osteochondromas, thus indicating the neoplastic origin of these lesions (Mertens et al, 1994;Bridge et al, 1998). In 1995, two separated studies found loss of heterozygosity for markers linked to EXT1 and EXT2, and suggested that osteochondromas development follows the Knudson's two-hit model for tumor suppressor gene inactivation Raskind et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation

et al. 2010

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Osteochondroma, the most common benign bone tumor, may occur as a sporadic lesion or as multiple neoplasms in the context of multiple osteochondromas syndrome. The most severe complication is malignant transformation into peripheral secondary chondrosarcoma. Although both benign conditions have been linked to defects in EXT1 or EXT2 genes, contradictory reports are present in the literature regarding the requirement of their biallelic inactivation for osteochondroma development. A major limitation of these studies is represented by the small number of samples available for the screening. Taking advantage of a large series of tissues, our aim was to contribute to the definition of a genetic model for osteochondromas onset and transformation. EXT genes point mutations and big deletions were analyzed in 64 tissue samples. A double hit was found in 5 out of 35 hereditary cases, 6 out of 16 chondrosarcomas and 2 recurrences; none of the 11 sporadic osteochondromas showed two somatic mutations. Our results clearly indicate that, in most cases, biallelic inactivation of EXT genes does not account for osteochondromas formation; this mechanism should be regarded as a common feature for hereditary osteochondromas transformation and as an event that occurs later in tumor progression of solitary cases. These findings suggest that mechanisms alternative to EXT genetic alteration likely have a role in osteochondromas pathogenesis.

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Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses

Cited by 64 publications

References 23 publications

Case Report Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings

Case Report Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings

Near-Haploidy and Subsequent Polyploidization Characterize the Progression of Peripheral Chondrosarcoma

Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation

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