Materiały źródłowe

• #1 Chordoma: an update on the pathophysiology and molecular mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4630230/

  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. […] For better understanding of the pathophysiology of this disease, studies have identified some genomic and epigenetic alterations underlying the development of chordoma, using robust techniques, such as comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), single nucleotide polymorphisms (SNP), and micro-ribonucleic acid (microRNA, miRNA, miR)-expression arrays. […] It has been generally accepted that chordoma cells originate from remnants of the embryonic notochord.

• #2

  https://www.orthobullets.com/evidence/26493697

  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.

• #2 Chordoma: an update on the pathophysiology and molecular mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4630230/

  It has been proposed that notochordal remnants are derived from the embryonic notochord since notochordal remnants are similar in size to notochord cells and reside in the region of the embryo in which the embryonic notochord was present. […] Since the occurrence of notochordal remnants in humans is much higher than the incidence of chordoma, it is presumed that notochordal remnants stay dormant in most cases but may transform into malignancies when stimulated by a mutation, environmental insult, or other events. […] The recent cancer stem cell (CSC) theory has shed more light on the embryonic transformations, which drives the notochordal cells to differentiate into the benign or malignant variant. […] The molecular events in chordomagenesis have not been fully delineated, particularly with respect to differentially expressed genes involved in the origin of chordoma.

• #3 Chordoma – Wikipedia

  https://en.wikipedia.org/wiki/Chordoma

  Chordoma is a rare slow-growing neoplasm (cancer) that arises from cellular remnants of the notochord in the bones of the skull base and spine. The evidence for the notochordal origin of chordoma is the location of the tumors (along the neuraxis), the similar immunohistochemical staining patterns, expression of brachyury, and the demonstration that notochordal cells are preferentially left behind in the clivus and sacrococcygeal regions when the remainder of the notochord regresses during fetal life. […] mTOR signaling is hyperactive in sporadic sacral chordomas: in one study 10 out of 10 sacral chordomas exhibited phosphorylation of Ribosomal protein s6 and EIF4EBP1 by immunohistochemistry. […] Partial or complete PTEN (gene) deficiency is observed in nearly all sacral chordomas. […] In a study of 49 chordomas Akt, TSC2, and EIF4EBP1 were phosphorylated in 92%, 96% and 98% of cases, respectively.

• #3 Chordoma: an update on the pathophysiology and molecular mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4630230/

  Recent studies are looking for novel mutations for better understanding of the molecular mechanisms and potentially identifying therapeutic targets. […] Chordoma is a cytogenetically heterogeneous tumor which displays complex karyotypes. […] Molecular cytogenetic studies have demonstrated that a variety of chromosomal markers exist in primary and recurrent chordomas, as well as frequent quantitative changes in the tumor cell genome. […] Brachyury is a transcription factor encoded by T gene in humans, a member of the T-box gene family. […] It helps with the promotion of cell movement and adhesion, which are fundamental for both morphogenesis and tumorigenesis. […] Long before it has been proposed as a unique specific diagnostic marker of chordoma, brachyury has been identified as a major regulator of notochord formation and a specific marker for the notochord and notochord-derived tumors.

• #4 Challenges in Diagnosing Chordoma (Skull Base Tumors) | IntechOpen

  https://www.intechopen.com/chapters/80398

  Chordomas may also be an outcome of direct malignant transformation of the notochordal remnant, deprived of a benign notochordal tumor intermediary stage. Otherwise chordoma may be inferred from benign notochordal cell tumor through malignant transformation (Figure 1) making another root of chordomagenesis. […] Ultimately, developing indication supports aberrant growth factor signaling as possible pathogenic mechanisms in chordoma. […] In general, it is believed that chordoma cells are initiated from the embryonic notochord remnants. It is also projected that notochordal remnants are derived from the embryonic notochord and reside in the region of an embryo where the embryonic notochord was existing. It is assumed that notochordal remnants stay dormant in maximum cases but might be transformed into malignancies. Yamaguchi and his colleagues have stated a link between persistent notochordal remnants and Chordoma.

• #4 Chordoma: an update on the pathophysiology and molecular mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4630230/

  Recent studies have shed lights on the genomic analysis in predicting chordoma growth and the ability to genetically modify or inhibit certain chromosomal loci or their protein products. […] The cell cycle aberrations have been proved to contribute to tumorigenesis and progression in many human malignancies, including chordoma. […] Fibroblast growth factor (FGF) has been found to be associated with chordoma pathophysiology. […] The FGFR/MEK/ERK/brachyury pathway has been proposed to coordinately regulate chordoma cell growth and survival and represent a novel chemotherapeutic target for chordoma. […] DNA methylation has already provided useful biomarkers for diagnosing cancer, monitoring treatment, and predicting the prognosis. […] Aberrant DNA hypermethylation of CpG islands in the promoter region of genes is well established as a common mechanism for the silencing of tumor suppressor genes and serve as an alternative mechanism of functional inactivation in malignances, including chordoma. […] As is known, miRNAs can act as either oncogenes or tumor suppressors in chordoma.

• #5 Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications in: Neurosurgical Focus Volume 56 Issue 5 (2024) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/56/5/article-pE18.xml

  Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. […] 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. […] Among the most clinically promising of molecular avenues uncovered is the role of brachyury in chordoma tumorigenesis. Brachyury is a T-box family transcriptional factor, transcribed from the TBXT gene on chromosome 6, implicated in early mesodermal development and subsequently concentrated in the evolving notochord.

• #6 Novel targeted therapies in chordoma: an update | TCRM

  https://www.dovepress.com/novel-targeted-therapies-in-chordoma-an-update-peer-reviewed-fulltext-article-TCRM

  Chordomas are rare, locally aggressive skull base neoplasms known for local recurrence and not-infrequent treatment failure. […] Progress in the understanding of chordomas molecular pathogenesis has given rise to efforts to treat chordomas with targeted therapies. […] Advances in the molecular understanding of chordomas have led to the identification of promising targetable pathways and prognostic markers. These include brachyury, receptor tyrosine kinases (RTKs), and downstream pathways. […] The brachyury or T gene located on chromosome 6q27 encodes a developmentally regulated transcription factor essential for notochordal development and formation of posterior mesodermal elements. […] Several lines of evidence also suggest a causative role of brachyury overexpression in chordoma formation.

• #7 Chordoma—Current Understanding and Modern Treatment Paradigms

  https://www.mdpi.com/2077-0383/10/5/1054

  Chordoma is a low-grade notochordal tumor of the skull base, mobile spine and sacrum which behaves malignantly and confers a poor prognosis despite indolent growth patterns. […] Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (e.g., platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (e.g., phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury—a transcription factor expressed ubiquitously in chordoma but not in other tissues—and the fibroblast growth factor [FGF]/mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] pathway.

• #8 Chordoma: Practice Essentials, History of the Disease, Epidemiology

  https://emedicine.medscape.com/article/250902-overview

  Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (eg, platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (eg, phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyurya transcription factor expressed ubiquitously in chordoma but not in other tissues, and the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. […] Immunohistochemical analysis of brachyury expression revealed that for classical and chondroid chordomas, the disease course cannot be reliably determined using only morphologic criteria. Brachyury (T gene) was shown to play a central role in chordoma pathogenesis.

• #8 Chordoma: Practice Essentials, History of the Disease, Epidemiology

  https://emedicine.medscape.com/article/250902-overview

  Chordomas can be divided into 4 subtypes: conventional, poorly differentiated, dedifferentiated, and chondroid. […] Different histologic subtypes of chordoma differ in their prognosis. To date, no recurrent genetic drivers have been identified for this disease. Brachyury seems to play a key role in the pathogenesis of chordoma, although the detailed mechanism remains to be elucidated. […] Genes implicated in chordoma formation include the brachyury gene and the mechanistic target of rapamycin (mTOR) signaling pathway, as well as deficiency of the phosphatase tensin homolog (PTEN) gene, INI1, and platelet-derived growth factor receptor-beta (PDGFR-beta), although no definitive genetic marker has yet been identified. […] A genetic basis has been described for some chordomas. However, most exhibit complex abnormal karyotypes, including whole or partial losses of chromosomes 3, 4, 10, and 13; gains in chromosome 7; and rearrangements of chromosome 1p.

• #9 Chordoma: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/chordoma/

  Changes in the TBXT gene have been associated with chordoma. An inherited duplication of the TBXT gene identified in a few families is associated with an increased risk of developing a chordoma. Duplications or increases in activity (expression) of the TBXT gene have also been identified in people with chordoma who have no history of the disorder in their family. […] The specific mechanism by which excess brachyury protein contributes to the development of chordomas is unclear. Some people with chordoma do not have changes in the TBXT gene, and the cause of the disorder in these individuals is unknown.

• #10 Pathology Outlines – Chordoma

  https://www.pathologyoutlines.com/topic/bonechordoma.html

  Malignant tumor with notochordal differentiation […] Most cases are sporadic but rare cases may be associated with benign notochordal tumor (Br J Radiol 2010;83:e49) […] T gene (brachyury) duplication (6q27) […] Familial associated tumors (autosomal dominant) are rare; they are associated with T gene duplication […] Rare cases associated with tuberous sclerosis; biallelic inactivation of TSC1 or TSC2 identified in the cases analyzed (Neurosurg Clin N Am 2015;26:437, Nat Rev Mol Cell Biol 2009;10:307) […] T gene (brachyury) duplication (6q27) occurs in ~27% of sporadic chordomas; however, nearly all notochordal tumors over express brachyury (epigenetic mechanisms) (Nat Commun 2017;8:890) […] Poorly differentiated chordoma: molecularly different from conventional chordoma and characterized for SMARCB1 deletion and subsequent loss of INI1 expression (Genes Chromosomes Cancer 2019;58:804) […] Poorly differentiated chordoma: heterozygous or homozygous deletions involving SMARCB1.

• #11 The driver landscape of sporadic chordoma | Nature Communications

  https://www.nature.com/articles/s41467-017-01026-0

  Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. […] The genetic basis of sporadic chordoma has been investigated using copy-number arrays and targeted sequencing limited to candidate genes. Collectively, these studies have identified recurrent loss of CDKN2A as a key driver in chordoma development. In addition, occasional alterations of PI3K signalling genes have been reported and evaluated in expression studies and in vitro.

• #12

  https://link.springer.com/article/10.1007/s40487-016-0016-0

  Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA and Europe (about 300 and 450 cases per year, respectively). […] The relationship of chordoma to the notochord was strengthened by the finding that brachyury, a transcription factor found in notochord tissue and essential for embryonic development, is overexpressed in chordoma. […] The role of epidermal growth factor receptor (EGFR) in chordoma pathogenesis: a potential therapeutic target. […] Brachyury appears to be an oncogenic driver of chordoma. […] The non-synonymous presence of the rs2305086 single nucleotide polymorphism was associated with increased risk of chordoma in one series. […] While nuclear brachyury expression remains useful to distinguish chordoma from tumors with similar morphologic features, it has become clear that brachyury is also expressed in other tumors, including epithelial tumors.

• #13 Understanding chordoma | Chordoma Foundation

  https://www.chordomafoundation.org/understanding-chordoma/

  Chordomas are complicated tumors to treat due to the involvement of critical structures such as the brainstem, spinal cord, and important nerves and arteries. […] For example, more than 95 percent of individuals with chordoma have a single-letter variation, called a SNP (snip), in the DNA sequence of a gene called brachyury (also known as TBXT). This SNP causes an increase in the risk of developing chordoma, but does not by itself cause chordoma. […] It is known that some of the families with familial chordoma have an extra copy of the brachyury gene, but currently, there is no available test for the presence of extra copies of the gene. […] Changes in either of two genes involved in Tuberous Sclerosis Complex (TSC1 and TSC2) can cause a predisposition to developing chordoma.

• #14

  https://link.springer.com/article/10.1007/s40487-016-0016-0

  In epithelial tumors, brachyury expression drives epithelial-to-mesenchymal transition, inducing stem-like features such as migration, invasiveness, and resistance to conventional therapy. […] The transcription factor brachyury in chordoma, agents like HDACi could potentially have an indirect effect on gene expression via epigenetic modulation.

• #15 Chordoma | Bone Cancer Research Trust

  https://www.bcrt.org.uk/information/information-by-type/chordoma/

  Chordomas have unusually high levels of a protein called brachyury that is normally found in the cells of the notochord, a precursor of the spinal cord. The brachyury gene (also called TBXT) which codes for the brachyury protein, is involved in controlling how the cells behave during human development; normally, after approximately 12 weeks, when its biological task is completed, the TBXT gene is switched off. If TBXT becomes reactivated in adulthood, it can contribute to the uncontrolled growth of cells and the development of cancer. […] Many chordoma patients have a gene irregularity, known as a mutation, in the brachyury gene which may be associated with chordoma development in both familial and sporadic forms of the tumour. Inheriting an extra copy of the brachyury gene is thought to be responsible for the familial form of chordoma in most cases.

• #16 Chordoma—Current Understanding and Modern Treatment Paradigms

  https://www.mdpi.com/2077-0383/10/5/1054

  The fibroblast growth factor (FGF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway mediates expression and signaling of brachyury in chordomas and may also play a role in chordomagenesis. […] Receptor tyrosine kinases (RTKs) are another area of interest in the pathogenesis of chordoma and other cancers. […] Dysfunctional signaling within an RTK cascade can thus lead to the aberrant behavior observed in tumor cells and oncogenic mutations have been documented in a number of different RTK families. […] With chordoma in particular, platelet-derived growth factor (PDGF) receptor (PDGFR), epidermal growth factor (EGF) receptor (EGFR) and hepatocyte growth factor (HGF) receptor (c-Met) are three RTKs thought to play a role in pathogenesis and malignant potential, as each has been shown to be overexpressed in chordoma.

• #17 Novel targeted therapies in chordoma: an update | TCRM

  https://www.dovepress.com/novel-targeted-therapies-in-chordoma-an-update-peer-reviewed-fulltext-article-TCRM

  Given the tight correlation between genomic aberrations of brachyury leading to its temporally aberrant reexpression in chordoma, brachyury may be considered to be a driver oncogene in chordoma. […] Reexpression of brachyury exclusively in chordoma, and its role in driving cancer behavior, makes brachyury an attractive target for therapeutic intervention. […] A large proportion of chordomas demonstrate EGFR overexpression, which is associated with aggressive clinical behavior. […] The PDGF receptor (PDGFR) is another PTK expressed in chordoma. […] Targeting PTKs in chordoma can be challenging, due to their multiplicity and functional redundancy. […] The rarity of skull-base chordomas limits not only the number of treatments that can be practically tested in clinical trials but also the statistical power required to identify meaningful differences in outcome.

• #18 (PDF) The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target

  https://www.academia.edu/113189521/The_role_of_epidermal_growth_factor_receptor_in_chordoma_pathogenesis_a_potential_therapeutic_target

  Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of chordoma. Paraffinembedded material from 173 chordomas from 160 patients was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative chordomas analysed by FISH, 38% revealed highlevel EGFR polysomy, 4% highlevel polysomy with focal amplification, 18% lowlevel polysomy, and 39% disomy. Phosphoreceptor tyrosine kinase array membranes showed EGFR activation in the chordoma cell line

• #19 (PDF) The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target

  https://www.academia.edu/113189521/The_role_of_epidermal_growth_factor_receptor_in_chordoma_pathogenesis_a_potential_therapeutic_target

  The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2a), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ERK pathway. […] The key genetic events responsible for the initiation and progression of chordomas remain to be discovered. […] We demonstrated that EGFR is frequently and the most significantly activated RTK in chordomas. Furthermore, concurrent to EGFR activation, the tumors commonly reveal co-activation of alternative RTK. The consistent activation of AKT, the frequent loss of the tumor suppressor PTEN allele, the recurrent activation of upstream RTK and of downstream effectors like p70S6K and mTOR, all indicate the PI3K/AKT pathway as an important mediator of transformation in chordomas.

• #20 Chordoma – Wikipedia

  https://en.wikipedia.org/wiki/Chordoma

  In a tissue microarray containing 21 chordomas Platelet-derived growth factor receptor-beta (PDGFR-b), epidermal growth factor receptor (EGFR), KIT (CD117) and HER2 were detected in 100%, 67%, 33% and 0% of cases, respectively. […] The CDKN2A (p16) and CDKN2B (p15) loci on chromosome 9p21 are frequently deleted in chordomas. […] 62% of chordomas express the High Molecular Weight Melanoma Associated Antigen, also known as Chondroitin sulfate proteoglycan 4 (CSPG4) which has been the target of immune therapy. […] In 2009, scientists discovered that an inherited gene duplication is responsible for the familial form of this disorder.

• #21 Chordoma—Current Understanding and Modern Treatment Paradigms

  https://www.mdpi.com/2077-0383/10/5/1054

  Furthermore, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is downstream of PDGFR, EGFR and c-Met and has been shown to be hyperactive in chordomas, suggesting that this pathway may be a unifying mechanism through which abnormal signaling by a variety of different RTKs underlies the pathophysiology of chordoma.

• #22 Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications in: Neurosurgical Focus Volume 56 Issue 5 (2024) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/56/5/article-pE18.xml

  In chordoma, brachyury expression has been correlated to both TBXT gene amplification and to PI3K/Akt pathway upregulation. […] The PI3K/Akt pathway may also synergize with other mechanisms of chordoma formation and propagation, including Sonic hedgehog (SHH). […] Although genomic alterations in SHH pathway genes are infrequent in chordoma, high expression of both SHH and Gli1 has been observed in both skull base and spinal chordoma. […] Perturbations to the SWI/SNF chromatin remodeling complex have considerable implications on both chordoma pathogenesis and therapeutic response. […] The presence of a distinct molecular subgroup of chordoma characterized by impaired chromatin regulation may help guide therapeutic selection particularly when considering immunotherapies. […] The significance of M1/M2 macrophage polarization and downstream functional dichotomies have been widely described across multiple cancers with the M1 phenotype frequently described by their phagocytic and proapoptotic function. […] Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression.

• #23 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Chordoma.aspx

  Research is still ongoing to understand the underlying mechanism behind the development of chordoma. […] The molecular mechanisms that lead to chordomagenesis have yet to be thoroughly elucidated, particularly in terms of differentially expressed genes implicated in chordomagenesis. […] Chordomas have been studied using G-banding, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) techniques to find chromosomal aberrations. […] In chordomas, several indicators that contribute to tumor progression have been identified. […] Brachyury is a T-box transcription factor that is encoded by the T or TBXT gene and has been proven to be important in notochord development. […] Furthermore, when compared to other neoplasms, chordoma is the only one that overexpresses brachyury. […] Chromosomal abnormalities occur in about half of all chordomas as late events in tumor growth. […] In chordoma, it appeared that losses were more common than gains.

• #24 Chordoma—Current Understanding and Modern Treatment Paradigms

  https://www.mdpi.com/2077-0383/10/5/1054

  Chordomas may theoretically arise from any anatomical location along the length of the notochord’s former embryological course. […] The precise mechanism underlying the transformation from notochordal vestige to chordoma is not well-understood, although recent studies have highlighted several chromosomal and cell cycle aberrations thought to contribute to chordomagenesis. […] Overexpression of both p53 and CDK4, for instance, which function in the G1 phase of the cell cycle, has been shown to be present in some chordomas and is correlated with decreased overall survival. […] The T gene (6p27) encodes brachyury, which, as mentioned previously, is a transcription factor required for notochord development from mesodermal elements. […] Brachyury is expressed transiently in embryonic notochord and normally silenced in post-developmental tissues but has been shown to be aberrantly re-expressed in chordoma and some evidence exists for its causative role in chordomagenesis.

• #25 Recurrent Chromosomal Copy Number Alterations in Sporadic Chordomas | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018846

  The molecular events in chordoma pathogenesis have not been fully delineated, particularly with respect to copy number changes. Understanding copy number alterations in chordoma may reveal critical disease mechanisms that could be exploited for tumor classification and therapy. […] Loss of CDKN2A with or without loss of CDKN2B on 9p21.3 was observed in 16/20 (80%) unique cases of which six (30%) showed homozygous deletions ranging from 76 kilobases to 4.7 megabases. […] Deficiency of CDKN2A and PTEN expression, although shared across many other different types of tumors, likely represents a key aspect of chordoma pathogenesis. Sporadic chordomas may rely on mechanisms other than copy number gain if they indeed exploit T/brachyury for proliferation. […] The frequent copy number losses of 9p and 10q in our cohort of tumors directed our investigation into the loss of gene expression of key tumor suppressor genes found in these two regions.

• #26 Recurrent Chromosomal Copy Number Alterations in Sporadic Chordomas | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018846

  The loss of 9p is an established finding in chordomas based on experiments involving FISH and BAC array CGH. The CDKN2A protein or p16, which is encoded by the CDKN2A gene on the short arm of chromosome 9 (9p21), is a tumor suppressor gene that inhibits the function of cdk4- and cdk6-cyclin D complexes. […] Review of our array CGH data showed various mechanisms of homozygous loss of CDKN2A only or CDKN2A/CDKN2B in 30% of our cases (excluding CH37), including submicroscopic deletions in the setting of 9p one copy loss. […] The PTEN tumor suppressor gene is located on 10q23.3, a region which showed hemizygous deletions in 80% of our chordoma samples. […] The findings indicate that the majority of sporadic chordomas may rely on mechanisms other than copy number gain if they indeed exploit T/brachury for proliferation.

• #27 Overexpression of adenosine deaminase acting on RNA 1 in chordoma tissues is associated with chordoma pathogenesis by reducing miR‑125a and miR‑10a expression

  https://www.spandidos-publications.com/10.3892/mmr.2015.3341

  Overexpression of adenosine deaminase acting on RNA 1 in chordoma tissues is associated with chordoma pathogenesis by reducing miR125a and miR10a expression. […] Emerging evidence suggests that microRNAs (miRs) are dysregulated in chordoma tissues and crucially involved in chordoma pathogenesis. […] Notably, the expression of the primary transcripts, primiR125a and primiR10a was unaltered, suggesting that disturbed microRNA expression may be induced by altered primiRNA processing. […] Therefore, the expression of ADAR1 and ADAR2 was analyzed in chordoma tissues. It was found that ADAR1 was significantly overexpressed, which was accompanied by enhanced premiR10a and primiR125a AtoI editing. These findings suggest that ADAR2 overexpression causes enhanced premiR10a and primiR125a AtoI editing, which alters mature miR10a and miR125a expression and may contribute to chordoma pathogenesis.

• #28 Overexpression of adenosine deaminase acting on RNA 1 in chordoma tissues is associated with chordoma pathogenesis by reducing miR‑125a and miR‑10a expression

  https://www.spandidos-publications.com/10.3892/mmr.2015.3341

  Previous studies have demonstrated that disturbed expression of miR-1 and miR-31 may be involved in chordoma pathogenesis, however, the mechanisms remain to be elucidated. […] In the present study, the expression levels of several miRNAs were detected, which have been reported to be dysregulated in chordoma, including miR-181a, miR-31, miR-1 and miR-146b. […] It was revealed that ADAR1 overexpression upregulated luciferase activity by reducing the expression of miR-125a and miR-10a, suggesting that ADAR1 is associated with cancer pathogenesis by reducing antitumor miRNAs. […] In conclusion, to the best of our knowledge, the present study is the first to demonstrate disturbed ADAR1 expression in chordoma tissues. Overexpression of ADAR1 is associated with chordoma pathogenesis by reducing tumor suppressor miRNA expression, including miR-125a and miR-10a expression.

• #29 Overexpression of adenosine deaminase acting on RNA 1 in chordoma tissues is associated with chordoma pathogenesis by reducing miR‑125a and miR‑10a expression

  https://www.spandidos-publications.com/10.3892/mmr.2015.3341?text=abstract

  Overexpression of adenosine deaminase acting on RNA 1 in chordoma tissues is associated with chordoma pathogenesis by reducing miR125a and miR10a expression. […] Emerging evidence suggests that microRNAs (miRs) are dysregulated in chordoma tissues and crucially involved in chordoma pathogenesis. […] Notably, the expression of the primary transcripts, primiR125a and primiR10a was unaltered, suggesting that disturbed microRNA expression may be induced by altered primiRNA processing. […] Therefore, the expression of ADAR1 and ADAR2 was analyzed in chordoma tissues. […] These findings suggest that ADAR2 overexpression causes enhanced premiR10a and primiR125a AtoI editing, which alters mature miR10a and miR125a expression and may contribute to chordoma pathogenesis. […] Previous studies have demonstrated that disturbed expression of miR-1 and miR-31 may be involved in chordoma pathogenesis, however, the underlying mechanisms remain to be elucidated.

• #30 Chordoma | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/chordoma?lang=us

  Chordomas are uncommon malignant tumors of the axial skeleton that account for 1% of intracranial tumors and 4% of all primary bone tumors. […] They originate from embryonic remnants of the primitive notochord (earliest fetal axial skeleton, extending from the Rathke’s pouch to the tip of the coccyx). […] Rare familial cases have also been described with mutations of the TBXT gene. […] Three subtypes are recognized: conventional chordoma (most common), chondroid chordoma (best prognosis), poorly and dedifferentiated chordoma (least common, worst prognosis). […] True malignant forms of chordomas occasionally have areas of typical chordoma as well as undifferentiated areas, most often fibrosarcoma. […] A number of genetic abnormalities have been described: duplication of TBXT gene, PIK3CA signaling mutations, LYST mutation, SMARCB1 gene homozygous deletion (poorly differentiated chordomas).

• #31 Chordoma | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/chordoma?lang=us

  Prognosis is typically poor due to the locally aggressive nature of these tumors, with overall 10-year survival of approximately 40%. […] Histological subtype also has a substantial impact on prognosis with chondroid chordoma having the best prognosis and dedifferentiated chordoma the worst prognosis; the more common conventional chordoma having intermediate prognosis.

• #32

  https://journals.lww.com/ajsp/fulltext/2020/09000/dedifferentiated_chordoma__clinicopathologic_and.7.aspx

  Dedifferentiated chordoma is a rare chordoma subtype characterized by a high-grade sarcoma juxtaposed to conventional chordoma. […] The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53 mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation.

• #33 Proteogenomic characterization of skull-base chordoma | Nature Communications

  https://www.nature.com/articles/s41467-024-52285-7

  Skull-base chordoma is a rare, aggressive bone cancer with a high recurrence rate. […] Here, we conduct integrative genomics, transcriptomics, proteomics, and phosphoproteomics analyses of 187 skull-base chordoma tumors. […] In our study, chromosome instability is identified as a prognostic predictor and potential therapeutic target. […] Multi-omics data reveals downstream effects of chromosome instability, with RPRD1B as a putative target for radiotherapy-resistant patients. […] Chromosome 1q gain, associated with chromosome instability and upregulated mitochondrial functions, lead to poorer clinical outcomes. […] Immune subtyping identify an immune cold subtype linked to chromosome 9p/10q loss and immune evasion. […] These findings, confirmed in 17 paired samples, provide insights into the biology and treatment of skull-base chordoma.

• #34 Proteogenomic characterization of skull-base chordoma | Nature Communications

  https://www.nature.com/articles/s41467-024-52285-7

  The pathogenesis of chordomas remains unclear. […] Most chordoma patients experience local recurrence, especially those with skull-base chordoma (SBC). […] The identification of predictive biomarkers of radiotherapy resistance in chordoma is urgently needed. […] Although widespread in most other tumors, CIN has not been comprehensively characterized in chordoma. […] Our study reveals the relationships between genetic alterations and transcriptional or translational regulation. […] These collective results indicated that variation in CIN status reflected the genetic heterogeneity among SBC patients, and could therefore potentially serve as a prognostic indicator and/or therapeutic target in treatments of SBC. […] Our findings suggested that a higher level of CIN might promote tumor proliferation in SBC.

• #35 Proteogenomic characterization of skull-base chordoma | Nature Communications

  https://www.nature.com/articles/s41467-024-52285-7

  The results demonstrated that cell cycle progression was promoted in CIN+ cells. […] The findings indicated that CIN could act as a genomic source for immune escape in SBC. […] The study demonstrated the significance of CIN status in predicting the prognosis and guiding following treatment strategies of SBC patients.

• #36 Targeting Chordoma Spinal Tumors Using Rational Drug Design | The Mark Foundation for Cancer Research

  https://themarkfoundation.org/portfolio/targeting-chordoma-spinal-tumors-using-rational-drug-design/

  There are currently no systemic therapies approved to treat chordoma, a rare bone cancer of the spine or base of the skull responsible for substantial morbidity and mortality of patients. The transcription factor brachyury is thought to drive chordoma pathogenesis, as well as contribute to metastatic potential in many other types of cancer. […] Because brachyury is minimally expressed in healthy adult tissue, the development of selective brachyury inhibitors is a promising targeted therapeutic strategy for chordoma. […] The ultimate goal of the project is the identification of one or more selective compounds that can be developed into a drug to treat chordoma.

• #37 Partial response to erlotinib in a patient with imatinib-refractory sacral chordoma | Clinical Sarcoma Research | Full Text

  https://clinicalsarcomaresearch.biomedcentral.com/articles/10.1186/s13569-020-00149-1

  Chordoma is a rare mesenchymal neoplasm which arises from the remnants of primitive notochord. […] There is preclinical evidence of the role of epidermal growth factor receptor (EGFR) in chordoma pathogenesis and also a few case reports elucidating the role of blocking this receptor leading to meaningful clinical responses. […] EGFR, a prototype receptor tyrosine kinase, plays a role in cell proliferation and survival. […] In order to elucidate the role of EGFR in pathogenesis of chordoma, Shalaby et al. demonstrated that gain of EGFR copy number is a common event in chordomas and that immunoreactivity for EGFR and p-EGFR is also a frequent finding. […] They could demonstrate growth inhibitory effect on chordoma cell lines harbouring a EGFR copy number gain by using a reversible tyrosine kinase inhibitor, thus highlighting that aberrant EGFR signalling may be involved in chordoma progression. […] The targeting of EGFR represents an attractive option in the limited therapeutic armamentarium against advanced chordomas.

• #38 (PDF) The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target

  https://www.academia.edu/113189521/The_role_of_epidermal_growth_factor_receptor_in_chordoma_pathogenesis_a_potential_therapeutic_target

  Given the complexity of the signaling in chordomas, combined treatment regimens targeting multiple RTK and downstream effectors are likely to be the most effective in these tumors. Personalized therapy with careful selection of the patients, based on the molecular profile of the specific tumor, is anticipated. […] Chordoma is a rare malignant bone tumour, showing notochordal differentiation, which occurs in the axial skeleton. Brachyury, a molecule involved in notochordal development, is a highly specific and sensitive marker for chordoma. It is hypothesised that brachyury or genes involved in its activation are implicated in the pathogenesis of chordoma. […] Immunohistochemistry showed that the PI3K/AKT/TSC/mTOR pathway was activated in 65% of chordomas, thereby providing a rationale for testing mTOR inhibitors for the treatment of selected cases. […] These findings demonstrate that brachyury plays an important role in chordoma pathology. […] Brachyury re-expression in notochord remnants is believed to play a major role in chordoma onset and maintenance and its expression is considered the main distinctive molecular marker of chordomas.

• #39 (PDF) The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target

  https://www.academia.edu/93454043/The_role_of_epidermal_growth_factor_receptor_in_chordoma_pathogenesis_a_potential_therapeutic_target

  Given the complexity of the signaling in chordomas, combined treatment regimens targeting multiple RTK and downstream effectors are likely to be the most effective in these tumors. […] Chordoma is a rare malignant bone tumour, showing notochordal differentiation, which occurs in the axial skeleton. Brachyury, a molecule involved in notochordal development, is a highly specific and sensitive marker for chordoma. It is hypothesised that brachyury or genes involved in its activation are implicated in the pathogenesis of chordoma. […] These findings demonstrate that brachyury plays an important role in chordoma pathology. […] Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. […] Afatinib was the only EGFR inhibitor with activity across the chordoma panel.

• #40 Challenges in Diagnosing Chordoma (Skull Base Tumors) | IntechOpen

  https://www.intechopen.com/chapters/80398

  Chordomas produce a plentiful extracellular matrix. […] Morphogens, signaling molecules that govern embryonic notochord development may play a key role to establish a cellular microenvironment that stimulates chordoma pathogenesis. […] Understanding of the molecular basis of chordoma pathophysiology hopefully will give us a better understanding to improve the prognosis of this rare malignancy.

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