Chordoma Pathogenesis Research Articles

A Case of Cervical Chordoma

A 48 year old male presented with neck pain and left arm pain that worsened with movement alongside left arm weakness, numbness, and tingling. The differential diagnosis for a patient with symptoms of a neck mass includes benign tumors like neurofibromas, malignant tumors like chordomas, and non-neoplastic conditions like cervical spondylitis. A magnetic resonance imaging (MRI) study of the cervical spine with and without contrast identified a T1 hypointense, T2 hyperintense, heterogeneously enhancing prevertebral mass with parapharyngeal extension. A direct laryngoscopy with biopsy was performed and revealed a paraspinal tumor. The patient’s diagnosis of cervical chordoma was confirmed upon detection of Brachyury, a gene that encodes a transcription factor which promotes epithelial mesenchymal transition (EMT) in chordoma pathogenesis. Chordomas are slow-growing tumors located within the body’s midline and they are associated with poorer outcomes because of neurovascular encasement at time of presentation. Chordomas are rare, with an incidence of 1 in 1,000,000. Approximately 6% of chordomas are located in the cervical spine. They are typically treated with surgery followed by radiation therapy. The patient underwent anterior resection for the prevertebral mass in the C2-C6 section of the cervical spinal cord. Surgery achieved subtotal resection and involved removal of the spinous processes of C3-C5 and reconstruction of the cervical spine with implants. The patient will be starting proton beam radiotherapy for his adjuvant treatment. Although rare, it is important to keep chordomas in the differential diagnosis when evaluating a patient with a neck mass.

Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.

Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.

N6-methyladenosine-modified circTEAD1 stabilizes Yap1 mRNA to promote chordoma tumorigenesis.

Chordoma, a rare bone tumour with aggressive local invasion and high recurrence rate with limited understanding of its molecular mechanisms. Circular RNAs (circRNAs) have been extensively implicated in tumorigenesis, yet their involvement in chordoma remains largely unexplored. N6-methyladenosine (m6A) modification holds a crucial function in regulating protein translation, RNA degradation and transcription. Initially, screening and validation of circTEAD1 in chordoma were conducted by high-throughput sequencing. Subsequently, sh-circTEAD1 and an overexpression plasmid were constructed. Colony formation assays, cell counting kit-8, Transwell and wound healing assays were utilized to validate the function of circTEAD1 in vitro. RNA pull-down assays identified the binding proteins of circTEAD1, which underwent verification through RNA immunoprecipitation (RIP). Methylated RIP assays were conducted to detect the m6A binding sites. Following this, luciferase assay, RT-qPCR, RIP and Western blotting analyses were conducted, revealing that Yap1 was the direct target of circTEAD1. Afterwards, the same methods were utilized for the validation of the function of Yap1 in chordoma in vitro. Finally, the regulatory relationship between circTEAD1 and Yap1 in chordoma was verified by an in vivo tumour formation assay. CircTEAD1 was identified as an upregulated circRNA in chordoma specimens, with heightened circTEAD1 expression emerging as a prognostic indicator. In vitro experiments convincingly demonstrated that circTEAD1 significantly promoted chordoma cell invasion, migration and aggressiveness. Furthermore, the analysis revealed that methyltransferase-like 3-mediated m6A modification facilitated the cytoplasmic export of circTEAD1. The circTEAD1/IGF2BP3/Yap1 mRNA RNA-protein ternary complex not only bolstered the stability of Yap1 mRNA but also exerted a pivotal role in driving chordoma tumorigenesis. In this study, the role of m6A-modified circTEAD1 in chordoma was identified. The findings offer novel insights into the potential molecular targets for chordoma therapy, shedding light on the intricate interplay between circRNAs, m6A modification and Yap1 mRNA in chordoma pathogenesis.

Abstract 3501: Concurrent amplification of TBXT and highly activated enhancers in extrachromosomal DNA (ecDNA) drives chordoma tumorigenesis

Abstract Chordoma, a rare bone cancer characterized by limited actionable clinical targets, exhibits a pivotal hallmark in the activation of the developmental transcription factor gene TBXT (Brachyury) through its association with highly active enhancers. TBXT amplification emerges as a major causative factor in familial chordomas, yet the amplification mechanism and its consequential impact on genomic instability remain inadequately elucidated. In this study, we conducted a comprehensive analysis of multiple genomic and epigenomic sequencing datasets, including WGS-seq, H3K27ac ChIP-seq, and ATAC-seq in six chordoma cell lines, and HiC data in two of them, to unravel the mechanisms of structural variations and their biological implications. Notably, our focus extends to JHC7 cells, which exhibit extrachromosomal amplification of a 2.4M region encompassing TBXT and the associated enhancers. The existence of such extrachromosomal DNA (ecDNA) in JHC7 was further validated through DNA FISH and Sanger sequencing. Comparing JHC7 with CH22, a chordoma cell line lacking TBXT amplification, revealed heightened chromatin relaxation and increased DNA rearrangements in JHC7. Interestingly, FISH results showed significant genomic ploidy heterogeneity within JHC7 cells, a finding demonstrated by nucleus FACS sorting. Single-cell multiomic analysis, combining snRNA-seq and snATAC-seq, demonstrated heterogeneous gene expression and distinct copy number variations among JHC7 cells. However, the amplification of the TBXT locus was observed in nearly all cells examined, indicating the rapid genomic evolution in the cultured JHC7 cells. These results collectively show that TBXT is extensively amplified through the formation of ecDNA, providing a fitness advantage to chordoma cells and concurrently exacerbating genomic instability. The findings in this study provide an insight for understanding the pathogenesis of chordoma and may inform the development of targeted therapeutic strategies. Citation Format: Bo Zhao, Martin Barrio Ines, Lingqun Ye, Xizi Wu, Alice Soragni, Andrew Futreal, Kadir Akdemir. Concurrent amplification of TBXT and highly activated enhancers in extrachromosomal DNA (ecDNA) drives chordoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3501.

Dysregulation of noncoding RNA in chordoma; implications in identifying potential targets for novel therapeutic approaches.

Chordoma is a rare form of bone cancer develops in the spinal cord and skull. Instead of conventional (radio/chemotherapies) and targeted therapies, the disease is associated with high rate of recurrence and poor patient survival. Thus, for better disease management, the molecular pathogenesis of chordoma should be studied in detail to identify dysregulated biomolecules that can be targeted by novel therapeutics. Recent research showed frequent dysregulation of long noncoding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) in association with aggressive tumor phenotypes like cell proliferation, migration, invasion, and metastasis in a variety of cancers, including chordoma. Apart from diagnostic and prognostic importance, noncoding RNAs may serve as promising targets for novel therapeutics in cancer. In this review, we summarized a list of miRNAs, lncRNAs, and circRNA found to be dysregulated in chordoma from available data published in relevant databases (PubMed), as such an approach seems to be rare to date. The dysregulated noncoding RNAs were also associated with adverse tumor phenotypes to assess the impact on disease pathogenesis and, associated downstream molecular pathways were focused. Synthetic compounds and natural products that were reported to target the noncoding RNAs in other malignancies were also listed from published literature and proposed as potential therapeutic agents in chordoma. This review will provide information for further research on chordoma focusing on detailed characterization of dysregulated lncRNAs, miRNAs, and circRNA to understand the disease pathogenesis and, exploration of suitable natural and synthetic products targeting dysregulated non-coding RNAs to develop effective therapeutic measures.

Dysregulated Epigenetics of Chordoma: Prognostic Markers and Therapeutic Targets.

Chordoma is a rare, slow-growing sarcoma that is locally aggressive and typically resistant to conventional chemo- and radiotherapies. Despite its low incidence, chordoma remains a clinical challenge because therapeutic options for chordoma are limited, and little is known about the molecular mechanisms involved in resistance to therapies. Furthermore, there are currently no established predictive or prognostic biomarkers to follow disease progression or treatment. Whole-genome sequencing of chordoma tissues has demonstrated a low-frequency mutation rate compared to other cancers. This has generated interest in the role of epigenetic events in chordoma pathogenesis. In this review, we discuss the current understanding of the epigenetic drivers of chordoma and their potential applications in prognosis and the development of new therapies.

XIST sponges miR-320d to promote chordoma progression by regulating ARF6

BackgroundLong non-coding RNAs (lncRNAs) have been demonstrated to play important roles in various tumors, including chordoma. The purpose of this study was to investigate the role and mechanism of lncRNA X-inactive specific transcript (XIST) in chordoma. MethodsRNA levels and protein levels were measured by real-time quantitative polymerase chain reaction (RT‑qPCR) and western blot assay, respectively. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2′-deoxyuridine (EdU) assay and colony formation assay. Tanswell assay was used to examine cell migration and invasion. Cellular glycolysis was examined via the measurement of extracellular acidification rate (ECAR) and lactate production. The interaction between microRNA-320d (miR-320d) and XIST or ADP-ribosylation factor 6 (ARF6) was predicted by bioinformatics analysis and verified by a dual-luciferase reporter and RNA-pull down assays. The xenograft tumor model was used to explore the biological function of XIST in vivo. ResultsXIST was overexpressed in chordoma tissues. XIST knockdown suppressed chordoma cell proliferation, migration, invasion, and glycolysis. XIST acted as a sponge of miR-320d. Moreover, miR-320d overexpression inhibited the proliferation, migration, invasion, and glycolysis of chordoma cells. ARF6 was a direct target of miR-320d, and XIST upregulated ARF6 expression via sponging miR-320d. Furthermore, overexpression of ARF6 reversed the inhibitory effects of XIST knockdown on chordoma cell proliferation, migration, invasion, and glycolysis. Importantly, XIST silencing blocked xenograft tumor growth in vivo. ConclusionXIST knockdown inhibited chordoma progression via regulating the miR-320d/ARF6 axis, providing a novel insight into chordoma pathogenesis.

Clinical and molecular features of sacrum chordoma in Chinese patients.

BackgroundChordoma is a rare malignant bone tumor with high recurrence and metastasis rates. Little is known about the mutational process of this incurable disease. The aim of our research was to explore the potential driver genes and signal pathways in the pathogenesis of chordoma and provide a new idea for the study of molecular biological therapy of chordoma.MethodsWe performed whole-exome-sequencing (WES) on 8 sacrum chordoma tissue samples (matched to peripheral blood samples that had been drawn from patients before surgery) to identify genetic alterations in Chinese patients. We analyzed the sequencing data from known driver genes, pathway enrichment analysis and significantly mutated genes (SMGs) after quality control of sequencing, comparison of reference genomes, analysis of mutations and identification of somatic mutations. Immunohistochemistry staining, Sanger sequencing and GeneChip were used to verify the related genes obtained from the analysis of sequencing data.ResultsThe driver genes Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), and Phosphatase And Tensin Homolog (PTEN) were enriched in the Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway and could be potential therapeutic targets for the treatment of sacrum chordoma. The significantly mutated gene Claudin 9 (CLDN9) may play a critical role in the development and progression of sacrum chordoma.ConclusionsCollectively, our results identified the genetic signature of sacrum chordoma and could be used to develop a potential promising therapeutic strategy for the treatment of sacrum chordoma in Chinese patients.

Association between TBXT rs2305089 polymorphism and chordoma in Iranian patients identified by a developed T-ARMS-PCR assay.

BackgroundChordoma is a locally aggressive bone tumor with a high capability of recurrence. Because chordoma often occurs at critical locations next to neurovascular structures, there is an urgent need to introduce validated biomarkers. T‐box transcription factor T (TBXT; OMIM: 601397) plays an important role in the pathogenesis and survival of chordoma cells.MethodsHerein, we aimed to show whether rs2305089 polymorphism is correlated with chordoma in the Iranian population. In order to detect rs2305089, tetra‐primer amplification refractory mutation system‐polymerase chain reaction (T‐ARMS‐PCR) was used. In total, 19 chordoma patients and 108 normal healthy individuals were recruited and screened using T‐ARMS‐PCR. The results were subsequently validated by Sanger sequencing.ResultsThe genotype distributions and allele frequencies were significantly different among the patient and healthy groups (p‐value <0.05). The A allele of rs2305089 showed a significant positive association with chordoma risk (p‐value <0.05). DNA sequencing verified the T‐ARMS‐PCR results as well. This study demonstrated the association between TBXT rs2305089 and chordoma in an Iranian population using a simple, accurate, and cost‐effective T‐ARMS‐PCR assay.ConclusionsOur results were in line with those of previous studies showing that TBXT rs2305089 is associated with chordoma development. We also developed an efficient T‐ARMS‐PCR assay to determine the genotype of rs2305089.

T-LAK cell-originated protein kinase (TOPK) is a Novel Prognostic and Therapeutic Target in Chordoma.

ObjectivesTo assess the expression, prognostic value, and functionality of T‐lymphokine‐activated killer (T‐LAK) cell‐originated protein kinase (TOPK) in chordoma pathogenesis.Materials and MethodsTOPK expression in chordoma was assessed via immunohistochemical staining of a tissue microarray (TMA) and correlated with patient clinicopathology. TOPK expression in chordoma cell lines and fresh patient tissues was then evaluated by Western blot. TOPK small interfering RNA (siRNA) and the specific inhibitor OTS514 were applied to determine the roles of TOPK in chordoma pathogenicity. The effect of TOPK expression on chordoma cell clonogenicity was also investigated using clonogenic assays. A 3D cell culture model was utilized to mimic in vivo environment to validate the effect of TOPK inhibition on chordoma cells.ResultsTOPK was highly expressed in 78.2% of the chordoma specimens in the TMA and all chordoma cell lines. High TOPK expression significantly correlated with metastasis, recurrence, disease status and shorter overall survival. Knockdown of TOPK with specific siRNA resulted in significantly decrease chordoma cell viability. Inhibition of TOPK with OTS514 significantly inhibited chordoma cell growth and proliferation, colony‐forming capacity and ex vivo spheroid growth.ConclusionsHigh expression of TOPK is an important predictor of poor prognosis in chordoma. Inhibition of TOPK resulted in significantly decrease chordoma cell proliferation and increase apoptosis. Our results indicate TOPK as a novel prognostic biomarker and therapeutic target for chordoma.

Skull base chordomas review of current treatment paradigms.

BackgroundChordomas are locally invasive neoplasms, arising from notochordal remnants and can appear anywhere along the axial skeleton. Local recurrences are common, and distant metastases may occur years after the initial presentation.MethodsLiterature review of current treatment strategies for chordomas of the skull base.ResultsSurgery is the mainstay of treatment and complete resection has paramount importance for prognosis.When complete resection is not achieved recurrent disease is common. The anatomical complexity of the skull base makes resection complex. Endonasal endoscopic approaches to the clivus has become increasingly favored in recent years although addressing reconstruction of the skull base to prevent CSF leak may be challenging.Evidence suggests that radiotherapy should not be considered as a primary single modality when trying to achieve cure of the disease. Nonetheless, immediate post-operative radiotherapy improves survival. Many strategies have been suggested to preserve sensitive vital structures in the skull base during treatment but as for survival there is no evidence of advantage when comparing adjuvant therapy with photon radiotherapy, gamma knife surgery, proton beam therapy, and carbon ion radiation therapy.There is no evidence to support cytotoxic chemotherapy in the treatment of chordomas but targeted therapies have started to show promise. Several optional molecular targets exist. Brachyury is overexpressed in 95% of chordomas but not in other mesenchymal neoplasms. However, its precise role in chordoma pathogenesis is currently unclear, and its cellular location in the nucleus makes it difficult to target. The inhibition of brachyury in chordoma cell lines induces growth arrest and apoptosis. This does not have clinical application to date. There are retrospective results with different molecular targeted therapies for advanced chordomas with some effectiveness.ConclusionDespite improvements made in the past 10 years in our knowledge of chordoma biology, available therapies still offer a limited benefit. There is an unmet need for new therapeutic options for patients with advanced disease. Therefore, patients with advanced disease should be encouraged to participate in clinical trials when and where available.

Chordome: Gibt es eine molekulargenetische Grundlage für Diagnostik und Therapie?

Chordomas are malignant bone tumours with areported annual incidence of 0.08 per 100,000 cases. They show anotochordal differentiation and are characterised by their nuclear expression of brachyury (TBXT). Chordomas are localised in the axial skeleton, where they occur from the clivus to the sacrococcygeal region. They are slow growing, locally destructive tumours, and are often not diagnosed until they have reached an advanced stage. Putative precursor-lesions are benign notochordal cell lesions, which are microscopically small and intraosseous. Different histological chordoma subtypes exist, which differ in their prognosis. To date, there are no known recurrent genetic drivers for this disease. Brachyury seems to play akey role in the pathogenesis of chordoma, though the detailed mechanism still needs to be elucidated. Surgical en bloc resection with negative margins is the only curative treatment for this disease. High-dose irradiation, particularly with protons and carbon ions, is atherapeutic alternative in cases of inoperable tumours. Currently, there is no approved medical treatment for chordoma. Clinical trials exploring additional therapeutic modalities are ongoing.

Chordoma: Etiology, Pathogenesis, Diagnosis, Treatment

The lecture analyzes modern knowledge about etiology, key mechanisms of pathogenesis, clinical manifestations, types, diagnostic methods and treatment strategy of chordoma (tumor from notochordal cells). To assess the retention of the lecture material, a case problem and multiple-choice test questions are given.

Role of the ECM in notochord formation, function and disease.

The notochord is a midline structure common to all chordate animals; it provides mechanical and signaling cues for the developing embryo. In vertebrates, the notochord plays key functions during embryogenesis, being a source of developmental signals that pattern the surrounding tissues. It is composed of a core of vacuolated cells surrounded by an epithelial-like sheath of cells that secrete a thick peri-notochordal basement membrane made of different extracellular matrix (ECM) proteins. The correct deposition and organization of the ECM is essential for proper notochord morphogenesis and function. Work carried out in the past two decades has allowed researchers to dissect the contribution of different ECM components to this embryonic tissue. Here, we will provide an overview of these genetic and mechanistic studies. In particular, we highlight the specific functions of distinct matrix molecules in regulating notochord development and notochord-derived signals. Moreover, we also discuss the involvement of ECM synthesis and its remodeling in the pathogenesis of chordoma, a malignant bone cancer that originates from remnants of notochord remaining after embryogenesis.

A focused compound screen highlights the significance of epidermal growth factor receptor signalling in chordoma pathogenesis.

Chordoma is a rare primary bone cancer with limited treatment options. Surgical resection followed by radiotherapy has proven effective; however, when, in 30-40% of patients, tumours recur and metastasize, a high level of resistance to chemotherapies leaves these patients with a dearth of treatment options. Recent work published in the Journal of Pathology by Scheipl et al describing a focused compound drug screen highlights the significance of epidermal growth factor receptor (EGFR) signalling in chordoma, and shows potential for EGFR inhibitors as a way forward for developing an effective treatment for chordoma. Importantly, combining EGFR inhibitors with a MET inhibitor induces a synergistic effect on growth inhibition of resistant chordoma cells, highlighting the significance of combined EGFR and MET inhibitors as a potential avenue to defeat chemoresistance in chordoma patients. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genomic aberrations frequently alter chromatin regulatory genes in chordoma.

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. © 2016 Wiley Periodicals, Inc.

Chordoma: Immunohistochemical Analysis of Brachury.

Chordomas are rare, slow growing but locally aggressive malignancies of the axial skeleton. Skull base chordomas, due to their intricate anatomical localization, pose significant challenges to managing physicians. In classical and chondroid chordomas, the disease course cannot be reliably determined using only morphological criteria. Brachyury (T Gene) was shown to play a central role in chordoma pathogenesis and several studies also showed that this gene also carries potential as a prognostic biomarker. This study aims to correlate Brachyury expression with the clinical course in surgically treated skull base chordomas. Chordoma tumor samples from 14 patients with skull base chordomas, diagnosed using histopathological and immunohistochemistry criteria (epithelial membrane antigen (EMA), S100, pan cytokeratin (panCK)) were retrospectively analyzed for Brachyury expression using immunohistochemistry. Brachyury expression was graded using a 4 point semi-quantitative scoring system. Focal (grade II) and diffuse staining (grade III) were considered as overexpression. Patient recurrence-free survival and total survival were compared between Brachyury overexpressing and non-overexpressing groups using Kaplan-Meier survival analysis. Among the stained tumor samples, 85.7% were positive for brachyury expression. In both groups, there was one sample that was negative. We did not observe any significant difference among the groups for staining, grade and percentage of brachyury positive cells. Brachyury expression in tumor samples is not a sensitive indicator of prognosis in chordomas.

The Role of EGFR, Hepatocyte Growth Factor Receptor (c-Met), c-ErbB2 (HER2-neu) and Clinicopathological Parameters in the Pathogenesis and Prognosis of Chordoma.

Chordoma is a rare malignant bone tumor with a poor outcome. Although radiotherapy and gamma knife surgery have been used for treatment, providing a cure for the tumor is not easy, because of the frequent recurrences. Molecular targeted therapy against tyrosine kinases has been effective in the treatment of malignancies such as breast and lung cancers and brain tumors. We aimed to analyse the histopathological features of chordomas and the immunoexpression profiles of the three receptor tyrosine kinases of EGFR, c-Met and c-Erb-B2 in chordomas. We have correlated these results with recurrence and overall survival status of the patients. We studied 49 chordoma patients in order to evaluate the histopathological features and immunohistochemical stainings by EGFR, c-Met and c-ErbB2 antibodies. Of the 49 patients, follow up data was available for 40 patients. Clinical data of the patients were correlated with histopathological features and survival analysis was performed. The immunostaining rate by EGFR and c-Met was 73.5% and 12.2% respectively. None of the cases showed immunoreactivity by c-ErbB2 (0%). Of the 40 cases, 17 cases showed recurrences. EGFR expression was detected in 14 recurrent (14/17) and 17 non-recurrent cases (17/23). Four of the 17 recurrent cases (4/17) were positive by c-Met, while none of the non-recurrent cases (0/23) were positive by this antibody. Significantly, all cases with positive c-Met expression showed recurrences (p < 0.05). Our study indicates that EGFR expression is detected in the majority of chordoma cases. c-Met expression can be used as a prognostic indicator for chordoma.

Chordoma: an update on the pathophysiology and molecular mechanisms.

Chordoma is a rare low-grade primary malignant skeletal tumor, which is presumed to derive from notochord remnants. The pathogenesis of chordoma has not been fully elucidated. However, recent advances in the molecular biology studies have identified brachyury underlying the initiation and progression of chordoma cells. More efforts have been made on accumulating evidence of the notochordal origin of chordoma, discovering signaling pathways and identifying crucial targets in chordomagenesis. In this review, we summarize the most recent research findings and focus on the pathophysiology and molecular mechanisms of chordoma.

Prognostic Significance of T Gene SNP s2305089 in Individuals with Spinal Column Chordoma

Introduction Chordoma is the most common primary spinal tumor with a median survival of 6 to 7 years, with high recurrence rates. Radical surgical resection remains the mainstay of treatment, with radiation often utilized to enhance local disease control. There are no approved chemotherapeutic agents for chordomas. Brachyury, coded by the T gene, has been implicated in the pathogenesis of chordomas and is highly expressed in most of these tumors. Recently, Pillay et al found that the single nucleotide polymorphism (SNP) rs2305089 in the T gene was associated with chordoma development. The variant A allele at rs2305089 results in a p.Gy177Asp change in Brachyury. Given the rarity of this disease, with an incidence of 0.08 per 100,000 individuals, determining the clinical significance of this SNP has been challenging. Materials and Methods This study included both prospective and retrospective data collected from five high-volume centers within Europe and North America. Data were collected between 1990 and 2013, through the AOSpine Knowledge Forum Tumor (AOSKFT) primary tumor database. Institutional approval was obtained before studying the tumor samples. Results In the overall cohort of 109 patients, survival at last follow-up (mean follow-up: 1,330 ± 1,475 days) was 69.7%. Seven (6.4%) patients had the GG genotype, while 66 (60.6%) and 36 (33.3%) patients had the AA and GA genotypes, respectively. In the 102 cases with the A variant, 75 (73.5%) were alive at the last follow-up compared with only 1 (14.3%) of the 7 patients with the GG genotype. Local recurrence rates were similar between the populations with the A variant and those without, with 40 (39.2%) patients with the A variant experiencing local recurrence compared with 2 (33.3%) patients without the A variant. Conclusions There is a trend toward worse survival in individuals with the GG genotype than with the AA or GA genotypes. To our knowledge, this is the first time the rs2305089 SNP has been considered in the prognosis and survival of individuals with chordoma.