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(searched for: doi:10.1038/sj.bjc.6604130)
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Jinhong Kim, Zhaolin Xu,
Published: 15 October 2021
npj Genomic Medicine, Volume 6, pp 1-15; https://doi.org/10.1038/s41525-021-00248-y

Abstract:
Lung cancer accounts for more than half of the new cancers diagnosed world-wide with poor survival rates. Despite the development of chemical, radiological, and immunotherapies, many patients do not benefit from these therapies, as recurrence is common. We performed single-cell RNA-sequencing (scRNA-seq) analysis using Fluidigm C1 systems to characterize human lung cancer transcriptomes at single-cell resolution. Validation of scRNA-seq differentially expressed genes (DEGs) through quantitative real time-polymerase chain reaction (qRT-PCR) found a positive correlation in fold-change values between C-X-C motif chemokine ligand 1 (CXCL1) and 2 (CXCL2) compared with bulk-cell level in 34 primary lung adenocarcinomas (LUADs) from Stage I patients. Furthermore, we discovered an inverse correlation between chemokine mRNAs, miR-532-5p, and miR-1266-3p in early-stage primary LUADs. Specially, miR-532-5p was quantifiable in plasma from the corresponding LUADs. Collectively, we identified markers of early-stage lung cancer that were validated in primary lung tumors and circulating blood.
Carolin Seeling, André Lechel, Michael Svinarenko, , Thomas F. E. Barth, Kevin Mellert
Journal of Experimental & Clinical Cancer Research, Volume 40, pp 1-14; https://doi.org/10.1186/s13046-021-02037-y

Abstract:
Background Tumor recurrence is one of the major challenges in clinical management of chordoma. Despite R0-resection, approximately 50% of chordomas recur within ten years after initial surgery. The underlying molecular processes are poorly understood resulting in the lack of associated therapeutic options. This is not least due to the absence of appropriate cell culture models of this orphan disease. Methods The intra-personal progression model cell lines U-CH11 and U-CH11R were compared using array comparative genomic hybridization, expression arrays, RNA-seq, and immunocytochemistry. Cell line origin was confirmed by short tandem repeat analysis. Inter-personal cell culture models (n = 6) were examined to validate whether the new model is representative. Cell viability after HOX/PBX complex inhibition with small peptides was determined by MTS assays. Results Using whole genome microarray analyses, striking differences in gene expression between primary and recurrent chordomas were identified. These expression differences were confirmed in the world’s first intra-personal model of chordoma relapse consisting of cell lines established from a primary (U-CH11) and the corresponding recurrent tumor (U-CH11R). Array comparative genomic hybridization and RNA-sequencing analyses revealed profound genetic similarities between both cell lines pointing to transcriptomic reprogramming as a key mechanism of chordoma progression. Network analysis of the recurrence specific genes highlighted HOX/PBX signaling as a common dysregulated event. Hence, HOX/PBX complexes were used as so far unknown therapeutic targets in recurrent chordomas. Treating chordoma cell lines with the complex formation inhibiting peptide HXR9 induced cFOS mediated apoptosis in all chordoma cell lines tested. This effect was significantly stronger in cell lines established from chordoma relapses. Conclusion Clearly differing gene expression patterns and vulnerabilities to HOX/PBX complex inhibition in highly therapy resistant chordoma relapses were identified using the first intra-personal loco-regional and further inter-personal chordoma progression models. For the first time, HOX/PBX interference was used to induce cell death in chordoma and might serve as the basic concept of an upcoming targeted therapy for chordomas of all progression stages.
Connor Liu, Ann Liu,
Published: 23 July 2021
Chordoma of the Spine pp 13-29; https://doi.org/10.1007/978-3-030-76201-8_2

The publisher has not yet granted permission to display this abstract.
Daniel J. Zabransky, Zach Pennington,
Published: 23 July 2021
Chordoma of the Spine pp 289-304; https://doi.org/10.1007/978-3-030-76201-8_16

The publisher has not yet granted permission to display this abstract.
Liang Wang, Xiaonan Guan, Qingtao Hu, Zhen Wu, Wei Chen, Lairong Song, Ke Wang, Kaibing Tian, Chunwei Cao, Dake Zhang, et al.
Published: 5 April 2021
Abstract:
Chordoma is a rare bone tumor arising from notochordal remnants, but the underlying mechanism remains elusive. By integrated mRNA and microRNA analyses, we found significant downregulation of TGFB3 along with upregulation of its inhibitor, miR-29 family in chordoma comparing with notochord. Somatic copy number gains of miR-29 loci in chordoma highlighted a mechanism of inactivation of TGFB3 signaling in tumor formation. In zebrafish, knockout and knockdown homologous tgfb3 resulted in a chordoma-like neoplasm. On the other hand, Smad7 negative feedback regulation of transforming growth factor-β (TGF-β) signaling is retentive in chordoma cell UM-Chor1 despite its disruption in most cancer cells (e.g. A549). Therefore, contrary to other cancers, exogenous TGF-β activated Smad7 by downregulating miR-182 and inhibited cell migration and invasion in UM-Chor1. Meanwhile, TGF-β decreased chordoma characteristic protein Brachyury. Altogether, downregulation of TGFB3 causes chordomagenesis, showing a feasible target for therapies. The retention of Smad7 negative regulation may maintain the suppressor role of TGF-β in chordoma.
, Jeff Ehresman, Edward F. McCarthy, A. Karim Ahmed, Patricia D. Pittman, Daniel Lubelski, C. Rory Goodwin,
Published: 1 March 2021
The Spine Journal, Volume 21, pp 500-517; https://doi.org/10.1016/j.spinee.2020.10.009

The publisher has not yet granted permission to display this abstract.
, Leslie Dodd, Jerzy Klijanienko
Journal of the American Society of Cytopathology, Volume 10, pp 278-292; https://doi.org/10.1016/j.jasc.2020.09.009

The publisher has not yet granted permission to display this abstract.
Samantha E. Hoffman, Sally A. Al AbdulMohsen, Saksham Gupta, , David M. Meredith, Ian F. Dunn,
Published: 8 July 2020
Frontiers in Neurology, Volume 11; https://doi.org/10.3389/fneur.2020.00657

Abstract:
Chordomas are rare tumors that are notoriously refractory to chemotherapy and radiotherapy when radical surgical resection is not achieved or upon recurrence after maximally aggressive treatment. The study of chordomas has been complicated by small patient cohorts and few available model systems due to the rarity of these tumors. Emerging next-generation sequencing technologies have broadened understanding of this disease by implicating novel pathways for possible targeted therapy. Mutations in cell-cycle regulation and chromatin remodeling genes have been identified in chordomas, but their significance remains unknown. Investigation of the immune microenvironment of these tumors suggests that checkpoint protein expression may influence prognosis, and adjuvant immunotherapy may improve patient outcome. Finally, growing evidence supports aberrant growth factor signaling as potential pathogenic mechanisms in chordoma. In this review, we characterize the impact on treatment opportunities offered by the genomic and immunologic landscape of this tumor.
Tumors and Tumor-Like Lesions of Bone pp 543-561; https://doi.org/10.1007/978-3-030-28315-5_42

The publisher has not yet granted permission to display this abstract.
, Jianjun Sun, Lei Yong, Chen Liang, Tie Liu, Yulun Xu, Jun Yang, Xiaoguang Liu
OncoTargets and Therapy, pp 4649-4663; https://doi.org/10.2147/ott.s252990

Abstract:
Introduction: Chordoma is a malignant tumor predominantly involving the skull base and vertebral column. This study aimed to investigate the molecular characteristics of PTEN and CDKN2A in conventional and chondroid chordomas and their correlation with clinical prognosis. Materials and Methods: A total of 42 patients were enrolled, including 26 patients with conventional chordoma and 16 patients with chondroid chordoma. Clinicopathological profiles and tissue specimens were collected. Gene sequencing and fluorescence in situ hybridization were performed to identify genetic alterations in the PTEN and CDKN2A genes. Immunohistochemical staining was used for semiquantitative evaluation of PTEN and CDKN2A expression. Results: Gene sequencing revealed an intron SNP (c.80– 96A>G) and a missense mutation (c.10G>A; p.Gly4Arg) in the PTEN gene and a missense mutation (c.442G>A; p.Ala148Thr) in the CDKN2A gene. Loss of the PTEN locus was identified in 25 (59.5%) cases, and loss of the CDKN2A locus was found in 28 (66.7%) cases. There was no significant correlation between progression-free survival (PFS)/overall survival (OS) and loss of PTEN or CDKN2A. The patients with lower PTEN expression showed significantly shorter PFS and OS than those with higher expression, while there was no significant difference in PFS or OS between patients with lower CDKN2A expression and those with higher CDKN2A expression. Conclusion: Our findings delineated the genetic landscape and expression of PTEN and CDKN2A in chordomas. PTEN expression may serve as a prognostic and predictive biomarker for chordomas.
Federico Gatto, Luis G. Perez-Rivas, Nicoleta Cristina Olarescu, Pati Khandeva, Konstantina Chachlaki, Giampaolo Trivellin, , , on behalf of the ENEA Young Researchers Committee (EYRC)
Published: 4 March 2020
Neuroendocrinology, Volume 110, pp 728-739; https://doi.org/10.1159/000506905

Abstract:
The parasellar region, located around the sella turcica, is an anatomically complex area representing a crossroads for important adjacent structures. Several lesions -including tumoral, inflammatory vascular- and infectious diseases may affect this area. Although invasive pituitary tumors are the most common neoplasms encountered within the parasellar region, other tumoral (and cystic) lesions can also be detected. Craniopharyngiomas, meningiomas, as well as Rathke's cleft cysts, chordomas, and ectopic pituitary tumors can primarily originate from the parasellar region. Except for hormone-producing ectopic pituitary tumors, signs and symptoms of these lesions are usually nonspecific, due to a mass effect on the surrounding anatomical structures (i.e. headache, visual defects), while a clinically relevant impairment of endocrine function (mainly anterior hypopituitarism and/or diabetes insipidus) can be present if the pituitary gland is displaced or compressed. Differential diagnosis of parasellar lesions mainly relies on magnetic resonance imaging, which should be interpreted by neuroradiologists skilled on base skull imaging. To date, neurosurgery is the main treatment, alone or in combination with radiotherapy. Of note, recent studies have identified gene mutations or signaling pathway modulators that represent potential candidates for the development of targeted therapies, particularly for craniopharyngiomas and meningiomas. In summary, parasellar lesions still represent a diagnostic and therapeutic challenge. A deeper knowledge of this complex anatomical site, the improvement of imaging tools, as well as novel insights in the pathophysiology of presenting lesions are strongly needed to improve the management of parasellar lesions. .
N. L. Michmerhuizen, J. H. Owen, M. E. Heft Neal, J. E. Mann, E. Leonard, J. Wang, J. Zhai, H. Jiang, J. B. McHugh, , et al.
Published: 17 February 2020
Journal of Neuro-Oncology, Volume 147, pp 25-35; https://doi.org/10.1007/s11060-020-03418-7

The publisher has not yet granted permission to display this abstract.
, Nadia Eden, Inga Usher, Patrick Lombard, Hongtao Ye, Lorena Ligammari, Daniel Lindsay, Sebastian Brandner, Jože Pižem, Nischalan Pillay, et al.
The Journal of Pathology: Clinical Research, Volume 6, pp 113-123; https://doi.org/10.1002/cjp2.156

Abstract:
The expression of p16/CDKN2A, the second most commonly inactivated tumour suppressor gene in cancer, is lost in the majority of chordomas. However, the mechanism(s) leading to its inactivation and contribution to disease progression have only been partially addressed using small patient cohorts. We studied 384 chordoma samples from 320 patients by immunohistochemistry and found that p16 protein was lost in 53% of chordomas and was heterogeneously expressed in these tumours. To determine if CDKN2A copy number loss could explain the absence of p16 protein expression we performed fluorescence in situ hybridisation (FISH) for CDKN2A on consecutive tissue sections. CDKN2A copy number status was altered in 168 of 274 (61%) of samples and copy number loss was the most frequent alteration acquired during clinical disease progression. CDKN2A homozygous deletion was always associated with p16 protein loss but only accounted for 33% of the p16‐negative cases. The remaining immunonegative cases were associated with disomy (27%), monosomy (12%), heterozygous loss (20%) and copy number gain (7%) of CDKN2A, supporting the hypothesis that loss of protein expression might be achieved via epigenetic or post‐transcriptional regulatory mechanisms. We identified that mRNA levels were comparable in tumours with and without p16 protein expression, but other events including DNA promoter hypermethylation, copy number neutral loss of heterozygosity and expression of candidate microRNAs previously implicated in the regulation of CDKN2A expression were not identified to explain the protein loss. The data argue that p16 loss in chordoma is commonly caused by a post‐transcriptional regulatory mechanism that is yet to be defined.
Benoîte Méry, Elise Rowinski, Mathilde Guinand, Marouan Benna, Amal Bousarsar, Claire Bosacki, Alexis Vallard,
Published: 24 December 2019
Bulletin du Cancer, Volume 107, pp 129-135; https://doi.org/10.1016/j.bulcan.2019.10.008

The publisher has not yet granted permission to display this abstract.
, Matteo Zoli, Federica Guaraldi, Giacomo Sollini, Antonella Bacci, Dino Gibertoni, , Luca Morandi, Ernesto Pasquini, , et al.
Published: 25 October 2019
Histopathology, Volume 76, pp 731-739; https://doi.org/10.1111/his.14024

The publisher has not yet granted permission to display this abstract.
, Alexandra S. Gersing, Thomas F. Barth, Melanie Boxberg, Klaus Woertler
Published: 18 May 2019
Skeletal Radiology, Volume 48, pp 2015-2020; https://doi.org/10.1007/s00256-019-03228-7

The publisher has not yet granted permission to display this abstract.
Tong Meng, Jiali Jin, Cong Jiang, Runzhi Huang, , , , Tong Meng, Jiali Jin, Cong Jiang, et al.
Published: 1 February 2019
Frontiers in Oncology, Volume 9; https://doi.org/10.3389/fonc.2019.00030

Abstract:
Objectives: Chordoma is a rare bone malignancy that affects the spine and skull base. Treatment dilemma leads to a high rate of local relapse and distant metastases. Molecular targeted therapy (MTT) is an option for advanced chordoma, but its therapeutic efficacy and safety have not been investigated systematically. Therefore, a systematic review was conducted on studies reporting MTT regimens for chordoma. Methods: Clinical trials, case series and case reports on chordoma MTT were identified using MEDLINE, Cochrane library and EMBASE, and systematically reviewed. Data on clinical outcomes, such as median overall survival, progression-free survival, response rate and adverse events (AEs) were extracted and analyzed. Results: Thirty-three eligible studies were selected for the systematic review, which indicated that imatinib and erlotinib were the most frequently used molecular targeted inhibitors (MTIs) for chordoma. For PDGFR-positive and/or EGFR-positive chordoma, clinical benefits were achieved with acceptable AEs. Monotherapy is preferred as the first-line of treatment, and combined drug therapy as the second-line treatment. In addition, the brachyury vaccine has shown promising results. Conclusions: The selection of MTIs for patients with advanced or relapsed chordoma should be based on gene mutation screening and immunohistochemistry (IHC). Monotherapy of TKIs is recommended as the first-line management, and combination therapy (two TKIs or TKI plus mTOR inhibitor) may be the choice for drug-resistant chordoma. Brachyury vaccine is a promising therapeutic strategy and requires more clinical trials to evaluate its safety and efficacy.
Gianluca D‘Agati, Elena María Cabello, , Elisabeth J. Rushing, Robin Klemm, , Richard M. White, ,
Disease Models & Mechanisms, Volume 12; https://doi.org/10.1242/dmm.039545

Abstract:
The aberrant activation of developmental processes triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Several potentially oncogenic factors have been found deregulated in chordoma, yet causation remains uncertain. In particular, sustained expression of the notochord regulator Brachyury is hypothesized as key driver of chordoma, yet experimental evidence is absent. Here, we apply a zebrafish chordoma model to identify the notochord-transforming potential of implicated genes in vivo. We find that Brachyury, including a form with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia. In contrast, the chordoma-implicated receptor tyrosine kinases EGFR and KDR/VEGFR2 are sufficient to transform notochord cells. Aberrant activation of RTK/Ras signaling attenuates processes required for notochord differentiation, including of the unfolded protein response and endoplasmic reticulum stress pathways. Our results provide first in vivo indication against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as possibly initiating event in chordoma. Further, our work points at modulating endoplasmic reticulum and protein stress pathways as possible therapeutic avenue against chordoma.
, Christopher Dardis, Adrienne Helland, Shobana Sekar, Jonathan Adkins, Lori Cuyugan, Daniel Enriquez, Sara Byron, Andrew S. Little
Molecular Case Studies, Volume 4; https://doi.org/10.1101/mcs.a003418

Abstract:
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.
Katharina Meditz,
Understanding Statistics and Experimental Design pp 61-73; https://doi.org/10.1007/978-3-319-74854-2_4

The publisher has not yet granted permission to display this abstract.
, Amanda Luck, Andrew Bondoc, Brian Golbourn, , , James Loukides, Nesrin Sabha, Christian Smith, , et al.
Published: 21 September 2018
The American Journal of Pathology, Volume 188; https://doi.org/10.1016/j.ajpath.2018.08.004

The publisher has not yet granted permission to display this abstract.
, , Masahiro Shin, Mayu Omata, Shunsaku Takayanagi, Shota Tanaka, Keisuke Ueki, Nobuhito Saito
Journal of Neurosurgery, Volume 128, pp 1428-1437; https://doi.org/10.3171/2016.12.jns161444

Abstract:
OBJECTIVE: Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma.METHODS: Brachyury gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of Brachyury high-expression tumors (n = 4) and Brachyury low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate Brachyury expression.RESULTS: All chordoma specimens expressed Brachyury, and expression levels varied widely. Patients with higher Brachyury expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with Brachyury expression (R = 0.61, p < 0.001). Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line.CONCLUSIONS: Activation of the PI3K/Akt pathway and Brachyury copy number gain are strongly associated with Brachyury overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.
, Paola Magnaghi, , Liviana Cozzi, Carlo Cusi, Fabio Bozzi, Nicola Beltrami, Giovanni Carapezza, Dario Ballinari, Nadia Amboldi, et al.
Published: 23 August 2017
Scientific Reports, Volume 7, pp 1-14; https://doi.org/10.1038/s41598-017-10044-3

Abstract:
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.
, Hiroki Imada, Shun Iida, Karoly Szuhai
Published: 29 June 2017
Surgical Pathology Clinics, Volume 10, pp 637-656; https://doi.org/10.1016/j.path.2017.04.008

The publisher has not yet granted permission to display this abstract.
Daniela Jäger, Thomas F. E. Barth, Silke Brüderlein, Angelika Scheuerle, Beate Rinner, , André Lechel, Patrick Meyer, Regine Mayer-Steinacker, Alexandra Von Baer, et al.
Published: 17 May 2017
Scientific Reports, Volume 7, pp 1-12; https://doi.org/10.1038/s41598-017-02174-5

Abstract:
Chordomas are rare tumours of the bone arising along the spine from clivus to sacrum. We compared three chordoma cell lines of the clivus region including the newly established clivus chordoma cell line, U-CH14, with nine chordoma cell lines originating from sacral primaries by morphology, on genomic and expression levels and with patient samples from our chordoma tissue bank. Clinically, chordomas of the clivus were generally smaller in size at presentation and patients with sacral chordomas had more metastases and more often recurrent disease. All chordoma cell lines had a typical physaliphorous morphology and expressed brachyury, S100-protein and cytokeratin. By expression analyses we detected differentially expressed genes in the clivus derived cell lines as compared to the sacral cell lines. Among these were HOXA7, HOXA9, and HOXA10 known to be important for the development of the anterior-posterior body axis. These results were confirmed by qPCR. Immunohistologically, clivus chordomas had no or very low levels of HOXA10 protein while sacral chordomas showed a strong nuclear positivity in all samples analysed. This differential expression of HOX genes in chordomas of the clivus and sacrum suggests an oncofetal mechanism in gene regulation linked to the anatomic site.
Yohei Kitamura, , Kazunari Yoshida
Published: 21 April 2017
Brain Tumor Pathology, Volume 34, pp 78-90; https://doi.org/10.1007/s10014-017-0283-y

The publisher has not yet granted permission to display this abstract.
M.N. Hayes, D.M. Langenau
Published: 1 January 2017
Methods in Cell Biology, Volume 138, pp 525-561; https://doi.org/10.1016/bs.mcb.2016.11.011

The publisher has not yet granted permission to display this abstract.
, In-Hee Lee, Sang Duk Hong, Doo-Sik Kong, Do-Hyun Nam
Published: 25 November 2016
Oncotarget, Volume 8, pp 1321-1328; https://doi.org/10.18632/oncotarget.13616

Abstract:
Skull base chordoma is a primary rare malignant bone-origin tumor showing relatively slow growth pattern and locally destructive lesions, which can only be characterized by histologic components. There is no available prognostic or therapeutic biomarker to predict clinical outcome or treatment response and the molecular mechanisms underlying chordoma development still remain unexplored. Therefore, we sought out to identify novel somatic variations that are associated with chordoma progression and potentially employed as therapeutic targets. Thirteen skull base chordomas were subjected for whole-exome and/or whole-transcriptome sequencing. In process, we have identified chromosomal aberration in 1p, 7, 10, 13 and 17q, high frequency of functional germline SNP of the T gene, rs2305089 (P = 0.0038) and several recurrent alterations including MUC4, NBPF1, NPIPB15 mutations and novel gene fusion of SAMD5-SASH1 for the first time in skull base chordoma.
Susanne Scheipl, Michelle Barnard, , Mette Jorgensen, , William J Zuercher, Fabrice Turlais, Hongtao Ye, Ana P Leite, James A Smith, et al.
Published: 22 April 2016
The Journal of Pathology, Volume 239, pp 320-334; https://doi.org/10.1002/path.4729

Abstract:
Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Published: 22 September 2015
Orphanet Journal of Rare Diseases, Volume 10, pp 1-10; https://doi.org/10.1186/s13023-015-0340-8

Abstract:
Paediatric chordomas are rare malignant tumours arising from primitive notochordal remnants with a high rate of recurrence. Only 5 % of them occur in the first two decades such less than 300 paediatric cases have been reported so far in the literature. In children, the average age at diagnosis is 10 years with a male-to-female ratio closed to 1. On the opposite to adults, the majority of paediatric chordomas are intracranial, characteristically centered on the sphenooccipital synchondrosis. Metastatic spread seems to be the prerogative of the under 5-year-old children with more frequent sacro-coccygeal locations and undifferentiated histology. The clinical presentation depends entirely on the tumour location. The most common presenting symptoms are diplopia and signs of raised intracranial pressure. Sacrococcygeal forms may present with an ulcerated subcutaneous mass, radicular pain, bladder and bowel dysfunctions. Diagnosis is suspected on computerised tomography showing the bone destruction and with typically lobulated appearance, hyperintense on T2-weighted magnetic resonance imaging. Today, treatment relies on as complete surgical resection as possible (rarely achieved because of frequent invasiveness of functional structures) followed by adjuvant radiotherapy by proton therapy. The role of chemotherapy has not been proven. Prognosis is better than in adults and depends on the extent of surgical resection, age and histology subgroup. Biological markers are still lacking to improve prognosis by developing targeted therapy.
, Ozlem Turksoy, Aysegul Kuskucu, Ugur Ture,
Published: 12 September 2015
Neurosurgical Review, Volume 39, pp 185-196; https://doi.org/10.1007/s10143-015-0663-x

The publisher has not yet granted permission to display this abstract.
Ke Wang, Zhen Wu, Kaibing Tian, Liang Wang, Shuyu Hao, Liwei Zhang, Junting Zhang
Published: 9 September 2015
Oncology Letters, Volume 10, pp 2937-2940; https://doi.org/10.3892/ol.2015.3687

Abstract:
Familial skull base chordoma is a rare tumor derived from the remnants of the embryonic notochord. The present study describes the clinical presentation of 4 cases of skull base chordomas in a family. A 15-year-old female received staged surgeries and was pathologically confirmed with a diagnosis of skull base chordoma. Among the patient's family, 2 members had previously undergone surgery and were pathologically confirmed with chordomas; 1 family member had also received radiation therapy. Furthermore, the patient's cousin, an 18-year-old male, was confirmed to have this condition by epipharyngoscopy. All confirmed cases within the family remained alive with the condition. A literature review of familial chordoma was undertaken and 8 chordoma pedigrees were found. Familial chordoma was rare, with an estimated rate of 0.4% in all chordomas. The skull base was the predominant location for familial chordoma. Compared with sporadic chordoma, familial chordomas were diagnosed at a younger age. The brachyury gene was strongly associated with familial chordomas, however, the exact pathogenesis and genetics mechanisms remains unclear.
Xin Yu, Zheng Li
Published: 10 August 2015
Cell Proliferation, Volume 48, pp 497-502; https://doi.org/10.1111/cpr.12204

Abstract:
Chordoma is a rare type of malignant bone tumour arising from remnant notochord and prognosis of patients with it remains poor as its molecular and genetic mechanisms are not well understood. Increasing evidence has demonstrated that epigenetic mechanisms (DNA methylation, histone modification and nucleosome remodelling), play a crucial role in the pathogenesis of many diseases. Aberrant epigenetic patterns are present in patients with chordoma, indicating a potential role for epigenetic mechanisms inthis malignancy. Furthermore, epigenetic alterations may provide novel biomarkers for diagnosis and prognosis as well as therapeutic targets for treatment. In this review, we discuss relevant epigenetic findings associated with chordoma, and their potential application for diagnosis, prognosis and treatment.
, Nils Mandahl
Published: 26 June 2015
Cancer Cytogenetics pp 566-582; https://doi.org/10.1002/9781118795569.ch23

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Elke V. Froehlich, , , Katharina Meditz, Heike Knausz, Katharina Troppan, Susanne Scheipl, , , Bernadette Liegl, et al.
Published: 30 January 2015
Journal of Orthopaedic Research, Volume 33, pp 771-778; https://doi.org/10.1002/jor.22819

Abstract:
Chordomas mainly arise along the axial skeleton and are characterized by their slow but destructive growth. Prognosis and quality of life are poor because treatment options are mainly limited to surgery and radiotherapy. Survivin, a member of the apoptosis inhibitor protein family, functions as a key regulator of mitosis and programmed cell death, and is overexpressed in many tumor types. The aim of this study was to determine the role of survivin in chordomas. Survivin expression was investigated in 50 chordoma samples and three chordoma cell lines using immunohistochemistry. The intensity of immunostaining was evaluated in regard to the development of recurrences. The immunohistochemical results were correlated with clinical parameters like gender, age, tumor size, and location and were performed in primary chordomas as well as in recurrent lesions. Furthermore, survivin knockdown experiments on chordoma cell lines were performed. YM155 decreased the growth behavior of chordoma cells dose- and time dependently. Transient knockdown of survivin led to a G2/M arrest, decreased proliferation, consistently induced an increase of polyploidy and morphological changes, and induced apoptosis. The resultant data from this study suggest that survivin plays a cell cycle-progressive role in chordomas. Hence, regulation of survivin by YM155 is a promising new target for the development of new therapeutic drugs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:771–778, 2015.
Tumors and Tumor-Like Lesions of Bone pp 533-553; https://doi.org/10.1007/978-1-4471-6578-1_39

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Carina Fischer, Susanne Scheipl, Agnes Zopf, Norbert Niklas, Alexander Deutsch, Mette Jorgensen, Birgit Lohberger, Elke Verena Froehlich, Andreas Leithner, , et al.
Journal of Cancer, Volume 6, pp 984-989; https://doi.org/10.7150/jca.11371

Abstract:
Background: Chordoma is a rare primary malignant bone tumour. Treatment options are mainly restricted to surgical excision, since chordomas are largely resistant to conventional ionising radiation and chemotherapy. Thus, there is a strong need to gain more thorough insights into the molecular biology and genetics of chordoma to allow for the development of new therapeutic options. We performed an ultra-deep sequencing analysis to find novel mutations in cancer associated genes in chordomas to date unseen with Sanger sequencing.
Posterior Fossa Tumors in Children pp 675-682; https://doi.org/10.1007/978-3-319-11274-9_44

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Jiyun Lee, Andrea R. Sternenberger, Shibo Li
Published: 1 January 2015
S. Scheil-Bertram
Published: 15 November 2014
Der Pathologe, Volume 35, pp 237-241; https://doi.org/10.1007/s00292-014-1986-z

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, , David Creytens, , Ruth Fleischeuer, René G.C. Santegoeds, Jacobus J. Van Overbeeke
Published: 1 July 2014
World Neurosurgery, Volume 82; https://doi.org/10.1016/j.wneu.2013.01.131

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Jason M. Davies, Aaron E. Robinson, Cynthia Cowdrey, Praveen V. Mummaneni, Gregory Ducker, Kevan M. Shokat, Andrew Bollen, Byron Hann,
Journal of Neurosurgery, Volume 120, pp 331-336; https://doi.org/10.3171/2013.10.jns13598

Abstract:
Object The management of patients with locally recurrent or metastatic chordoma is a challenge. Preclinical disease models would greatly accelerate the development of novel therapeutic options for chordoma. The authors sought to establish and characterize a primary xenograft model for chordoma that faithfully recapitulates the molecular features of human chordoma. Methods Chordoma tissue from a recurrent clival tumor was obtained at the time of surgery and implanted subcutaneously into NOD-SCID interleukin-2 receptor gamma (IL-2Rγ) null (NSG) mouse hosts. Successful xenografts were established and passaged in the NSG mice. The recurrent chordoma and the derived human chordoma xenograft were compared by histology, immunohistochemistry, and phospho-specific immunohistochemistry. Based on these results, mice harboring subcutaneous chordoma xenografts were treated with the mTOR inhibitor MLN0128, and tumors were subjected to phosphoproteome profiling using Luminex technology and immunohistochemistry. Results SF8894 is a novel chordoma xenograft established from a recurrent clival chordoma that faithfully recapitulates the histopathological, immunohistological, and phosphoproteomic features of the human tumor. The PI3K/Akt/mTOR pathway was activated, as evidenced by diffuse immunopositivity for phospho-epitopes, in the recurrent chordoma and in the established xenograft. Treatment of mice harboring chordoma xenografts with MLN0128 resulted in decreased activity of the PI3K/Akt/mTOR signaling pathway as indicated by decreased phospho-mTOR levels (p = 0.019, n = 3 tumors per group). Conclusions The authors report the establishment of SF8894, a recurrent clival chordoma xenograft that mimics many of the features of the original tumor and that should be a useful preclinical model for recurrent chordoma.
, , Alexandra VON Baer, Erich Hartwig, Michael Sarkar, , Silke Brüderlein, Bettina Westhoff, Ingo Melzner, Birgit Bassaly, et al.
International Journal of Oncology, Volume 44, pp 1041-1055; https://doi.org/10.3892/ijo.2014.2268

Abstract:
The molecular basis of chordoma is still poorly understood, particularly with respect to differentially expressed genes involved in the primary origin of chordoma. In this study, therefore, we compared the transcriptional expression profile of one sacral chordoma recurrence, two chordoma cell lines (U-CH1 and U-CH2) and one chondrosarcoma cell line (U-CS2) with vertebral disc using a high-density oligonucleotide array. The expression of 65 genes whose mRNA levels differed significantly (p<0.001; ≥6-fold change) between chordoma and control (vertebral disc) was identified. Genes with increased expression in chordoma compared to control and chondrosarcoma were most frequently located on chromosomes 2 (11%), 5 (8%), 1 and 7 (each 6%), whereas interphase cytogenetics of 33 chordomas demonstrated gains of chromosomal material most prevalent on 7q (42%), 12q (21%), 17q (21%), 20q (27%) and 22q (21%). The microarray data were confirmed for selected genes by quantitative polymerase chain reaction analysis. As in other studies, we showed the expression of brachyury. We demonstrate the expression of new potential candidates for chordoma tumorigenesis, such as CD24, ECRG4, RARRES2, IGFBP2, RAP1, HAI2, RAB38, osteopontin, GalNAc-T3, VAMP8 and others. Thus, we identified and validated a set of interesting candidate genes whose differential expression likely plays a role in chordoma.
, Derrick T. Lin, Josh Meier, Aaron Remenschneider, Marc Herr, Stacey T. Gray
Laryngoscope Investigative Otolaryngology, Volume 124, pp 1097-1102; https://doi.org/10.1002/lary.24420

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Yohei Kitamura, Hikaru Sasaki, Tokuhiro Kimura, Tomoru Miwa, , Takeshi Kawase, Kazunari Yoshida
Journal of Neuropathology & Experimental Neurology, Volume 72, pp 816-823; https://doi.org/10.1097/nen.0b013e3182a065d0

Abstract:
The official journal of the American Association of Neuropathologists, Inc. Publishes original articles on neuropathology and experimental neuroscience, book re
Yohei Kitamura, , Tokuhiro Kimura, Tomoru Miwa, Satoshi Takahashi, Takeshi Kawase, Kazunari Yoshida
Journal of Neuropathology & Experimental Neurology, Volume 72, pp 814-821; https://doi.org/10.1093/jnen/72.9.814

Abstract:
Chordomas are invasive tumors that develop from notochordal remnants and frequently occur in the skull base. The T gene and its product (brachyury) have recently been suggested to play an important role in chordoma progression. To date, few studies have investigated the relationship between the molecular/genetic characteristics of chordoma and patient prognosis. We analyzed 37 skull base chordomas for chromosomal copy number aberrations using comparative genomic hybridization, brachyury expression by immunohisto-chemistry, and T gene copy number by fluorescence in situ hybridization. The results of these molecular analyses and clinical parameters were compared with the patients' clinical courses. Univariate analyses using the log-rank test demonstrated that losses on chromosome 1p and gains on 1q and 2p were negatively correlated with progression-free survival, as were factors such as female sex, partial tumor removal, lack of postoperative irradiation, and high MIB-1 index. Expression of brachyury and copy number gain of the T gene were also significantly associated with shorter progression-free survival. Multivariate analysis using the Cox hazards model showed that lack of irradiation, gain on chromosome 2p, and expression of brachyury were independently associated with a poor prognosis. Our results suggest that brachyury-negative chordomas are biologically distinct from brachyury-positive chordomas and that T/brachyury might be an appropriate molecular therapeutic target for chordoma.
, G. Köhler
Published: 3 July 2013
Der Onkologe, Volume 19, pp 629-634; https://doi.org/10.1007/s00761-013-2479-z

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