Mutation Analysis of Nine Chordoma Specimens by Targeted Next-Generation Cancer Panel Sequencing

Fischer, Carina; Scheipl, Susanne; Zopf, Agnes; Niklas, Norbert; Deutsch, Alexander; Jørgensen, Mette; Lohberger, Birgit; Froehlich, Elke Verena; Leithner, Andreas; Gabriel, Christian; Liegl‐Atzwanger, Bernadette; Rinner, Beate

doi:10.7150/jca.11371

Cited by 16 publications

(14 citation statements)

References 26 publications

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“…Also, the four Chor-IN-1 tumor-specific variants were not present in the other chordoma cell lines. Therefore, we were unable to identify somatic mutations distinctive of chordoma, in line with what has already been published in literature 19 , 20 .…”

Section: Resultssupporting

confidence: 55%

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: Resultssupporting

confidence: 55%

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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“…Our work demonstrates that integrated and comprehensive DNA and RNA profiling is practical on archival chordoma samples and that such an approach aids in the identification of potential candidate therapeutic targets. Previous genetic studies of chordoma have reported somatic abnormalities in genes such as CDKN2A , PTEN , PIK3CA , and TP53 (Hallor et al 2008; Choy et al 2014; Fischer et al 2015; Wang et al 2016). Similar to previous studies, we did not observe highly recurrent somatic alterations; however, we identified alterations in genes that have been previously associated with chordoma, including PBRM1 (Wang et al 2016) and IGF1R (Sommer et al 2010; Scheipl et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…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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“…Previous mutation screening studies in chordoma have been more limited in genomic scope. Choy et al studied 45 chordoma samples for 865 “hotspot” mutations in 111 oncogenes using the mass spectrum Sequenom iPLEX genotyping platform (Choy et al, ) and Fischer et al screened for mutations in 48 cancer genes on 9 chordoma samples using an amplicon‐based targeted next‐generation sequencing platform (Fischer et al, ). A few mutations were reported, however, the alteration frequency in their study set was extremely low, typically presenting in <2 samples in each study cohort.…”

Section: Discussionmentioning

confidence: 99%

Genomic aberrations frequently alter chromatin regulatory genes in chordoma

Wang

Zehir

Nafa

et al. 2016

Genes Chromosomes & Cancer

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Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a ~8 Mb segment at 3p21.1–p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (~23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (~40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes.

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Mutation Analysis of Nine Chordoma Specimens by Targeted Next-Generation Cancer Panel Sequencing

Cited by 16 publications

References 26 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 aberrations frequently alter chromatin regulatory genes in chordoma

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