Genomic Profiling of Chondrosarcoma: Chromosomal Patterns in Central and Peripheral Tumors

Hallor, Karolin H.; Staaf, Johan; Bovée, Judith; Hogendoorn, Pancras C.W.; Cleton‐Jansen, Anne‐Marie; Knuutila, Sakari; Savola, Suvi; Niini, Tarja; Brosjö, Otte; Bauer, Henrik C. F.; Steyern, Fredrik Vult von; Jonsson, Kjell; Skorpil, Mikael; Mandahl, Nils; Mertens, Fredrik

doi:10.1158/1078-0432.ccr-08-2330

Cited by 72 publications

(68 citation statements)

References 32 publications

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“…9,10,15,16,19,23 However, to the best of our knowledge, the present study offers the first case series of whole-genome analysis of a rare subset of chondrosarcomas arising in the skull base. The median patient age among our cases was slightly older than that in the largest case study (200 cases) of SBCS (50 vs 39 years, respectively).…”

Section: Discussionmentioning

confidence: 87%

“…9,10,15,16,19,23 In addition, 8q24.1-qter and 14q24-qter were correlated with shorter overall survival in patients with extracranial chondrosarcomas; 15 a loss of 6 and gain of 12q12 were associated with higher grade chondrosarcomas; 23 and losses of 5q14.2-q21.3, 6q16-q25.3, 9p24.2-p12, and 9p21.3 were associated with higher grade tumors. 10 In comparison with these data for extracranial cases, our series of SBCSs showed frequent gains of 8q21.1 and 19 in 3 of the 7 cases.…”

Section: Discussionmentioning

confidence: 99%

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Genetic characterization of skull base chondrosarcomas

Kanamori¹,

Kitamura²,

Kimura

et al. 2015

JNS

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A lthough chondrosarcoma is the third most frequent primary malignancy of bone after myeloma and osteosarcoma, 7 skull base chondrosarcomas (SBCSs) are rare, accounting for only approximately 1% of all chondrosarcomas. 6 In France, intracranial chondrosarcomas account for 0.05% of all brain tumors, 21 and together with chordoma, they account for 0.09% of central nervous system tumors in the United States.5 However, among malignant bone tumors in the skull base, SBCS and chordoma are the 2 major histological types. Distinction of these 2 tumors is important, because SBCSs of the skull base are reported to show significantly better prognosis than chordomas. 1,4 Clinicians and pathologists are occasionally confronted by diagnostic problems caused by radiological and histological overlap between SBCSs and chordomas, especially with the "chondroid" subtype of chordomas. Recently, brachyury, a new immunohistochemical marker for chordoma, has been used to help distinguish chordomas from chondrosarcomas in addition to traditional markers, including cytokeratin and epithelial membrane antigen (EMA). 18Little is known about the genetic characteristics of SBCSs, because unlike for chordomas and extracranial chondrosarcomas, there have been no reports of whole-genome analysis of a case series of SBCSs to date. An early cytogenetic study of a single case of SBCS was described, obJect Although chondrosarcomas rarely arise in the skull base, chondrosarcomas and chordomas are the 2 major malignant bone neoplasms occurring at this location. The distinction of these 2 tumors is important, but this distinction is occasionally problematic because of radiological and histological overlap. Unlike chordoma and extracranial chondrosarcoma, no case series presenting a whole-genome analysis of skull base chondrosarcomas (SBCSs) has been reported. The goal of this study is to clarify the genetic characteristics of SBCSs and contrast them with those of chordomas. methods The authors analyzed 7 SBCS specimens for chromosomal copy number alterations (CNAs) using comparative genomic hybridization (CGH). They also examined IDH1 and IDH2 mutations and brachyury expression. results In CGH analyses, the authors detected CNAs in 6 of the 7 cases, including chromosomal gains of 8q21.1, 19, 2q22-q32, 5qcen-q14, 8q21-q22, and 15qcen-q14. Mutation of IDH1 was found with a high frequency (5 of 7 cases, 71.4%), of which R132S was most frequently mutated. No IDH2 mutations were found, and immunohistochemical staining for brachyury was negative in all cases. coNclusioNs To the best of the authors' knowledge, this is the first whole-genome study of an SBSC case series. Their findings suggest that these tumors are molecularly consistent with a subset of conventional central chondrosarcomas and different from skull base chordomas.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Genetic characterization of skull base chondrosarcomas

Kanamori¹,

Kitamura²,

Kimura

et al. 2015

JNS

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“…Seventeen sporadic peripheral chondrosarcomas, well-known for not showing point mutations in the EXT genes (Bove´e et al, 1999;Hallor et al, 2009;Zuntini et al, 2010), were collected to study DNA copy-number alterations by using a custom-made Agilent oligonucleotide-based microarray containing 44 000 probes with a tiling coverage of EXT1/2 genes and additional 68 genes involved in heparan and chondroitin sulfate biosynthesis as described by Szuhai et al (2011). Only alterations of EXT genes were investigated.…”

Section: Ext Tiling Arraymentioning

confidence: 99%

“…Secondary peripheral chondrosarcomas are malignant cartilage-producing tumors. Contrary to what is observed in osteochondromas, homozygous inactivations of the EXT genes are detected in a much smaller subset (B15%) of secondary peripheral chondrosarcomas (Hecht et al, 1995;Raskind et al, 1995;Bove´e et al, 1999;Hallor et al, 2009;Zuntini et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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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“…Additionally, IDH1/IDH2 mutations are shown not to be involved in secondary peripheral chondrosarcomas formation [76]. Malignant progression of secondary peripheral chondrosarcomas is characterized by a high percentage of loss of heterozygosity (ie CDKN2A/p16, TP53, RB1 ) and ploidy ranging from half to twice the normal DNA content [77][78][79]. It suggests that p16, p53 and RB1 are involved in neoplastic transformation of an osteochondroma.…”

Section: Micro-environment Promoting and Inducing Secondary Peripheramentioning

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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Genomic Profiling of Chondrosarcoma: Chromosomal Patterns in Central and Peripheral Tumors

Cited by 72 publications

References 32 publications

Genetic characterization of skull base chondrosarcomas

Genetic characterization of skull base chondrosarcomas

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

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