Molecular profiling of chordoma

Scheil-Bertram, S.; Kappler, Roland; Baer, Alexandra von; Hartwig, E.; Sarkar, Michael R.; Serra, Massimo; Brüderlein, Silke; Westhoff, Bettina; Melzner, Ingo; Bassaly, Birgit; Herms, Jochen; Hugo, Heinz-Hermann; Schulte, M.; Möller, Peter

doi:10.3892/ijo.2014.2268

Cited by 47 publications

(23 citation statements)

References 30 publications

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“…The mRNA expression profiling of our 8 cell lines revealed high mRNA levels of typical chordoma markers, including brachyury, collagen 2A1, and CD24 (32,43). When compared with the NCI-60 cancer cell line panel and other public available mRNA expression data the chordoma cell lines clustered together confirming the characteristic profile of these tumors.…”

Section: Discussionmentioning

confidence: 69%

Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway

et al. 2015

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Chordomas are tumors that arise at vertebral bodies and the base of the skull. Although rare in incidence, they are deadly owing to slow growth and a lack of effective therapeutic options. In this study, we addressed the need for chordoma cell systems that can be used to identify therapeutic targets and empower testing of candidate pharmacologic drugs. Eight human chordoma cell lines that we established exhibited cytology, genomics, mRNA, and protein profiles that were characteristic of primary chordomas. Candidate responder profiles were identified through an immunohistochemical analysis of a chordoma tissue bank of 43 patients. Genomic, mRNA, and protein expression analyses confirmed that the new cell systems were highly representative of chordoma tissues. Notably, all cells exhibited a loss of CDKN2A and p16, resulting in universal activation of the CDK4/6 and Rb pathways. Therefore, we investigated the CDK4/6 pathway and responses to the CDK4/6-specific inhibitor palbociclib. In the newly validated system, palbociclib treatment efficiently inhibited tumor cell growth in vitro and a drug responder versus nonresponder molecular signature was defined on the basis of immunohistochemical expression of CDK4/6/pRb (S780). Overall, our work offers a valuable new tool for chordoma studies including the development of novel biomarkers and molecular targeting strategies. Cancer Res; 75(18); 3823-31. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 69%

Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway

et al. 2015

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“…In our previous report, 14 skull base chordomas frequently showed losses on 1p, 3p, 9, 10, 13q, 14q, and 18q and gains on 1q, 2p, 7, and17q, most of which were also reported by other researchers as major abnormalities in chordomas. 17,24,25 These CNAs were absent or only rarely observed in our SBCS series, implying that the profile of CNAs in SBCS is at least partially different from that in chordomas.…”

Section: Discussionmentioning

confidence: 93%

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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“…These investigators found that 65 genes were expressed differentially. CD24, ECRG4, RARRES2, RAP1, HAI2, RAB38, IGFBP2, osteopontin, GalNAc-T3, and VAMP8 were found to be major potential candidate genes, and their differential expression may play a role in the development of a chordoma [92].…”

Section: Gene Expression and Cell Signalingmentioning

confidence: 99%

The molecular aspects of chordoma

et al. 2015

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Chordomas are one of the rarest bone tumors, and they originate from remnants of embryonic notochord along the spine, more frequently at the skull base and sacrum. Although they are relatively slow growing and low grade, chordomas are highly recurrent, aggressive, locally invasive, and prone to metastasize to the lungs, bone, and the liver. Chordomas highly and generally show a dual epithelial-mesenchymal differentiation. These tumors resist chemotherapy and radiotherapy; therefore, radical surgery and high-dose radiation are the most used treatments, although there is no standard way to treat the disease. The molecular biology process behind the initiation and progression of a chordoma needs to be revealed for a better understanding of the disease and to develop more effective therapies. Efforts to discover the mysteries of these molecular aspects have delineated several molecular and genetic alterations in this tumor. Here, we review and describe the emerging insights into the molecular landscape of chordomas.

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Molecular profiling of chordoma

Cited by 47 publications

References 30 publications

Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway

Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway

Genetic characterization of skull base chondrosarcomas

The molecular aspects of chordoma

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