Genomic and transcriptomic characterization of skull base chordoma

Jason, K.; Lee, In Hee; Hong, Sang Duk; Kong, Doo Sik; Nam, Do Hyun

doi:10.18632/oncotarget.13616

Cited by 22 publications

(14 citation statements)

References 33 publications

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“…Similarly, trisomy of chr7, clearly evidenced also by karyotype analysis of the Chor-IN-1, is a feature shared by all the chordoma cell lines with the exception of JHC7, which bears a partial chr7 trisomy involving only the long arm. This trisomy was previously reported in a significant fraction of chordoma clinical samples 25 , 26 . Interestingly, the EGFR gene is located in the short arm of chr7 and is therefore not affected by the partial trisomy in the JHC7 cell line.…”

Section: Discussionsupporting

confidence: 79%

Establishment and genomic characterization of the new chordoma cell line Chor-IN-1

Bosotti¹,

Magnaghi²,

Bella³

et al. 2017

Sci Rep

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Chordomas are rare, slowly growing tumors with high medical need, arising in the axial skeleton from notochord remnants. The transcription factor “brachyury” represents a distinctive molecular marker and a key oncogenic driver of chordomas. Tyrosine kinase receptors are also expressed, but so far kinase inhibitors have not shown clear clinical efficacy in chordoma patients. The need for effective therapies is extremely high, but the paucity of established chordoma cell lines has limited preclinical research. Here we describe the isolation of the new Chor-IN-1 cell line from a recurrent sacral chordoma and its characterization as compared to other chordoma cell lines. Chor-IN-1 displays genomic identity to the tumor of origin and has morphological features, growth characteristics and chromosomal abnormalities typical of chordoma, with expression of brachyury and other relevant biomarkers. Chor-IN-1 gene variants, copy number alterations and kinome gene expression were analyzed in comparison to other four chordoma cell lines, generating large scale DNA and mRNA genomic data that can be exploited for the identification of novel pharmacological targets and candidate predictive biomarkers of drug sensitivity in chordoma. The establishment of this new, well characterized chordoma cell line provides a useful tool for the identification of drugs active in chordoma.

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Section: Discussionsupporting

confidence: 79%

Establishment and genomic characterization of the new chordoma cell line Chor-IN-1

Bosotti¹,

Magnaghi²,

Bella³

et al. 2017

Sci Rep

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“…Previous analyses have led to the identification of pathological changes in chordomas. Such changes include transcriptomic changes (Bell et al 2016), as well as point mutations and copy-number losses in genes such as ALK , CDKN2A , NRAS , PTEN , NBPF1 , SETD2 , and SMARCB1 (Hallor et al 2008; Le et al 2011; Choy et al 2014; Fischer et al 2015; Wang et al 2016; Sa et al 2017; Cote et al 2018), whose loss characterizes poorly differentiated chordomas (Mobley et al 2010). Of note, loss of INI1/SMARCB1 may also represent a discrete entity with a more aggressive phenotype more similar to rhabdoid tumors (Hasselblatt et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Identification of therapeutic targets in chordoma through comprehensive genomic and transcriptomic analyses

Liang

Dardis

Helland

et al. 2018

Cold Spring Harb Mol Case Stud

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Chordoma is a rare, orphan cancer arising from embryonal precursors of bone. Surgery and radiotherapy (RT) provide excellent local control, often at the price of significant morbidity because of the structures involved and the need for relatively high doses of RT; however, recurrence remains high. Although our understanding of the genetic changes that occur in chordoma is evolving rapidly, this knowledge has yet to translate into treatments. We performed comprehensive DNA (paired tumor/normal whole-exome and shallow whole-genome) and RNA (tumor whole-transcriptome) next-generation sequencing analyses of archival sacral and clivus chordoma specimens. Incorporation of transcriptomic data enabled the identification of gene overexpression and expressed DNA alterations, thus providing additional support for potential therapeutic targets. In three patients, we identified alterations that may be amenable to off-label FDA-approved treatments for other tumor types. These alterations include FGFR1 overexpression (ponatinib, pazopanib) and copy-number duplication of CDK4 (palbociclib) and ERBB3 (gefitinib). In a third patient, germline DNA demonstrated predicted pathogenic changes in CHEK2 and ATM, which may have predisposed the patient to developing chordoma at a young age and may also be associated with potential sensitivity to PARP inhibitors because of homologous recombination repair deficiency. Last, in the fourth patient, a missense mutation in IGF1R was identified, suggesting potential activity for investigational anti-IGF1R strategies. Our findings demonstrate that chordoma patients present with aberrations in overlapping pathways. These results provide support for targeting the IGF1R/FGFR/EGFR and CDK4/6 pathways as treatment strategies for chordoma patients. This study underscores the value of comprehensive genomic and transcriptomic analysis in the development of rational, individualized treatment plans for chordoma.

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“…All but one of the patients in this study who presented recurrent fusions fell under the non-high-risk category; thus, it is likely that these fusions have not been reported because most of the previous studies included only high-risk patients. These fusions have been detected in other cancers [10,11] and further research is needed to investigate the potential roles of these fusions in the tumorigenesis of NB.…”

Section: Discussionmentioning

confidence: 99%

Genomic profile of MYCN non-amplified neuroblastoma and potential for immunotherapeutic strategies in neuroblastoma

Lee

et al. 2020

Preprint

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Background MYCN amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification.Results Fifty-eight whole exome sequencing (WES) and 48 whole transcriptome sequencing (WTS) samples of MYCN non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs. In the MYCN non-amplified NB WES data, maximum recurrent mutations were found in MUC4 (26%), followed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32-CBX3 (10%) and SAMD5-SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair (MMR) associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients.Conclusions This study provides novel insights into the genomic background of MYCN non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB.

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Genomic and transcriptomic characterization of skull base chordoma

Cited by 22 publications

References 33 publications

Establishment and genomic characterization of the new chordoma cell line Chor-IN-1

Establishment and genomic characterization of the new chordoma cell line Chor-IN-1

Identification of therapeutic targets in chordoma through comprehensive genomic and transcriptomic analyses

Genomic profile of MYCN non-amplified neuroblastoma and potential for immunotherapeutic strategies in neuroblastoma

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