Materiały źródłowe

• #1 Rhabdomyosarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507721/

  Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma that is believed to originate from primitive mesenchymal cells that typically differentiate into skeletal tissue. […] The etiology and risk factors remain largely unknown. Most cases of rhabdomyosarcoma are sporadic; however, the disease can be associated with familial syndromes. […] Although the etiology of rhabdomyosarcoma is largely unknown, there is evidence of an underlying genetic component because a chromosomal translocation has been identified in many RMS tumors, and RMS has been associated with several inherited cancer syndromes (eg, Noonan, Li-Fraumeni, Beckwith-Wiedemann, and Costello. […] An increased risk of developing RMS is also seen with other factors, including fetal radiation exposure, parental drug use, family history of RMS in a first-degree relative, preterm birth, fertility drug use, and history of congenital defects.

• #2 Pediatric Rhabdomyosarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/988803-overview

  Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin that is included in the group of small round blue cell tumors of childhood along with neuroblastoma, lymphoma and primitive neuroectodermal tumors. The name is derived from the Greek words rhabdo, which means rod shape, and myo, which means muscle. […] Although Weber first described rhabdomyosarcoma in 1854, a clear histologic definition was not available until 1946, when Stout recognized the distinct morphology of rhabdomyoblasts. […] As its name suggests, the tumor is believed to arise from a primitive muscle cell. Rhabdomyoblasts sometimes have discernible muscle striations that are visible on specimens under light microscopy, although electron microscopy may be needed to detect subcellular elements. […] The tumor is believed to arise from primitive muscle cells, but tumors can occur anywhere in the body; however, a primary bone rhabdomyosarcoma has not been reported.

• #3 Genetic Characterization, Current Model Systems and Prognostic Stratification in PAX Fusion-Negative vs. PAX Fusion-Positive Rhabdomyosarcoma

  https://www.mdpi.com/2073-4425/12/10/1500

  Importantly, RMS can occur at sites that lack skeletal muscle, such as the salivary gland, gallbladder, and bladder, which places a true skeletal, muscle-derived origin into question. […] The Sonic hedgehog (SHH) pathway is critical in early stages of skeletal muscle development, and many studies have shown its importance in ERMS pathogenesis. […] Several FN-RMS models have shown to be associated with aberrant SHH signaling. […] Another important gene in embryonic and postnatal skeletal myogenesis is NOTCH1. […] The third important player in embryonic signaling pathways affecting skeletal muscle development is WNT. […] More recently, the MAPK pathway in RAS-driven FN-RMS was shown to promote RMS pathogenesis while inhibiting MYOG expression. […] The mTOR pathway seems to contribute to RMS invasion, while inhibition of it seems to diminish cellular migration, invasion and angiogenesis in RMS models. […] Within the last few decades, significant progress has been made regarding the understanding of myogenesis and, thus, what may underlie the pathogenesis of RMS.

• #4 Molecular pathogenesis of rhabdomyosarcoma – PubMed

  https://pubmed.ncbi.nlm.nih.gov/12170781/

  Rhabdomyosarcoma (RMS) is a family of soft tissue tumors that are associated with the skeletal muscle lineage and generally occur in the pediatric population. […] Based on histopathologic features, two subtypes, embryonal (ERMS) and alveolar (ARMS), were identified and associated with distinct clinical characteristics and genetic alterations. ARMS is associated with 2;13 or 1;13 chromosomal translocations, which generate PAX3-FKHR and PAX7-FKHR fusion products, respectively. These translocations result in altered expression, function, and subcellular localization of the fusion products relative to the wild-type proteins, and ultimately contribute to oncogenic behavior by modifying growth, differentiation, and apoptosis pathways. […] In contrast to the specific translocations found in ARMS, most ERMS cases have allelic loss at chromosome 11p15.5. Chromosome fragment transfer studies demonstrated that this region represses tumor cell growth, suggesting the presence of tumor suppressor gene(s) in this region. In both ERMS and ARMS, there is evidence of collaborating alterations that affect common targets, such as the p53 and RB pathways. One mechanism for perturbing these pathways involves amplification of genes such as MDM2 and CDK4; these amplification events occur frequently in ARMS but only rarely in ERMS. Therefore, despite similarities in the downstream targets of these genetic alterations, the striking cytogenetic and molecular differences between ARMS and ERMS indicate distinct molecular etiologies in these two subtypes.

• #5 Pathology – Rhabdomyosarcoma: Practice Essentials, Histology, Presentation and Evaluation

  https://emedicine.medscape.com/article/873546-overview

  Rhabdomyosarcoma is a malignant tumor of striated muscle origin. […] According to Rubin, it is derived from primitive mesenchyme that retained its capacity for skeletal muscle differentiation. […] Embryonal rhabdomyosarcoma has unique molecular characteristics. Embryonal rhabdomyosarcoma cells show a loss of specific genome material from the short arm of chromosome 11. This consistent loss of the material from the 11p15 region may suggest the presence of a tumor suppressor gene, though the actual gene responsible for embryonal rhabdomyosarcoma is not yet known. Another molecular feature is its lack of gene amplification. In addition, the cellular DNA content of embryonal rhabdomyosarcoma is hyperdiploid (1.1-1.8 X normal DNA). […] Like embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma has distinct molecular characteristics. A unique translocation occurs between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (70%) or the PAX7 gene on chromosome 1 (30%).

• #6 Pediatric Rhabdomyosarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/988803-overview

  The alveolar variant is so named because of the thin criss-crossing fibrous bands that appear as spaces between cellular regions of the tumor (reminiscent of lung alveoli). This variant is usually associated with 1 of 2 chromosomal translocations, namely, t(2;13) or t(1;13). […] These result in the fusion of the DNA-binding domain of the neuromuscular developmental transcription factors, encoded by PAX3 on chromosome 2 or PAX7 on chromosome 1, to the transcriptional activation domain of a relatively ubiquitous transcription factor, FKHR (or FOXO1a), which is encoded on chromosome 13. […] The resulting hybrid molecule is a potent transcription activator. It is believed to contribute to the cancerous phenotype by abnormally activating or repressing other genes. […] The embryonal subtype usually has a loss of heterozygosity at band 11p15.5; this observation suggests the presence of a tumor suppressor gene. Other molecular aberrations that may provide clues to the origin of the tumor and that may be useful for future treatment strategies include TP53 mutations (which occur in approximately one half of patients), an elevated N-myc level (in 10% of patients with ARMS), and point mutations in N-ras and K-ras oncogenes (usually embryonal). […] In addition, levels of insulinlike growth factor-2 may be elevated, suggesting pathways involving autocrine and paracrine growth factors.

• #7 Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings

  http://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1665-11462016000600405

  The aggressive behavior of alveolar rhabdomyosarcoma has been associated with the expression of oncogenic fusion proteins resulting from chromosomal translocations, particularly t(2;13) (q35;q14) PAX3/FOXO1, and t(1;13) (p36;q14) PAX7/FOXO1 which were present in this patient. […] The most common chromosomal translocation found in ARMS is t(2;13) (q35;q14) PAX3/FOXO1, and the less frequently found is t(1;13) (p36;q14) PAX7/FOXO1. […] The translocations t(2;13) and t(1;13) result from the breakdown of specific genes that are within the chromosomic region 2q35 and 1p36, respectively, followed by fusion. […] The fusion of these genes leads to the expression of fusion proteins, which act as transcriptional activators that contribute to tumor development by altering pathways of cell growth and apoptosis, modulating the myogenic differentiation, and stimulating motility and other metastatic pathways.

• #8 Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings

  http://www.scielo.org.mx/scielo.php?script=sci_arttext&pid=S1665-11462016000600405

  The mechanisms by which the chimeric protein PAX/FOXO1 contributes to oncogenesis of the RMS have been deeply studied. […] Both PAX3/FOXO1 and PAX7/FOXO1 have a transcriptional activity 100 times greater than the wild proteins PAX3 and PAX7. […] The overexpression of PAX3 results from an increase in the transcription that is independent of the number of copies, while the high expression of PAX7 is associated with gene amplification. […] Another way in which the protein PAX/FOXO1 contributes in the oncogenesis is by preventing the tumor cell apoptosis through the expression of anti-apoptotic genes as Bcl-XL. […] The main problem in the biology of rhabdomyosarcomas is their susceptibility to differentiate into skeletal muscle indefinitely, which is the result of alterations in the myogenic program, at the kinases (i.e., p38 MAPK) and the epigenetic level. […] The prognosis of patients with RMS depends on the grade of the tumor, age, type of resection, histology, presence of the mentioned translocations and number of sites with metastases.

• #9 Soft Tissues: Embryonal rhabdomyosarcoma

  https://atlasgeneticsoncology.org/solid-tumor/5193/soft-tissues-embryonal-rhabdomyosarcoma

  Embryonal rhabdomyosarcoma (ERMS) refers to one subtype of the rhabdomyosarcoma family of soft tissue tumors. These are mesenchymal tumours related to the skeletal muscle lineage. […] In many cases, ERMS occurs in regions without abundant or in some cases, regions without any detectable skeletal muscle. Therefore, the relationship of ERMS to skeletal muscle is not clear. However, it is postulated that ERMS is derived from mesenchymal precursors of mesodermal origin. […] In contrast to the recurrent chromosomal translocations found in ARMS, ERMS does not have recurrent structural chromosome rearrangements, but rather has frequent chromosome gains. The most notable gains in ERMS were chromosomes 2, 8, 11, 12, 13, and 20. […] It is postulated that one allele of a tumor suppressor gene in this region is physiologically inactivated by imprinting and the second allele is removed by the allelic loss event, and thus both alleles of the tumor suppressor are inactivated to promote an oncogenic effect.

• #10 New insights into signalling-pathway alterations in rhabdomyosarcoma | British Journal of Cancer

  https://www.nature.com/articles/bjc2014471

  Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and young adults. Several recent studies have shed new light on the alterations in signalling pathways and the downstream effects of these pathway alterations in RMS. […] Many studies have highlighted the importance of the PAX-FOXO1 fusion in ARMS biology. […] The impact of signalling-pathway alterations in RMS was recently reinforced in a genome-wide study, which characterised the profile of somatic alterations in 147 RMS tumour samples. […] The authors also found that alteration of the receptor tyrosine kinase/RAS/phosphoinositide 3-kinase (PI3K) axis affected 93% of RMS cases and that alterations in this axis appeared to hinge on the FGF and IGF receptor pathways. […] The study also revealed two additional novel recurrent mutations in F-Box and WD repeat domain containing 7 (FBXW7) and BCL6 co-repressor (BCOR) genes, in addition to previously identified mutations in the RAS, FGFR4, PIK3CA, and CTNNB1 genes.

• #11 New insights into signalling-pathway alterations in rhabdomyosarcoma | British Journal of Cancer

  https://www.nature.com/articles/bjc2014471

  Fibroblast growth factors are highly overexpressed in RMS and function to drive proliferation. […] Recent work has shown that FGF signalling can rescue a subset of ARMS cells from apoptosis induced by compounds targeting the IGF1-RPI3KmTOR pathway. […] The work suggests that inhibition of FGF signalling may offer a new approach to enhance the efficiency of RMS treatments. […] The precise role of IGF in RMS cells is unclear, but IGF clearly promotes the proliferation of RMS cells and blocks to IGF signaling suppress the growth of RMS cells in vivo. […] The IGF2 locus shows a loss of imprinting in both ERMS and ARMS tumours and expression of PAX3-FOXO1 can induce the upregulation of IGF2, thus enhancing the activation of IGF signalling pathway in ARMS. […] Many of the cell signalling pathways such as FGF and IGF converge on cell-cycle regulators such as the cell-cycle regulator cyclin-dependent kinase (Cdk) inhibitor p21CIP1/WAF1 (CDKN1A), hence referred to as p21, and the cell-cycle regulator p14ARF (human) or p19ARF (murine; CDKN2A).

• #12 Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies

  https://www.mdpi.com/2072-6694/15/21/5269

  In fusion-positive (FP) RMS, the PAX3-FOXO1 and PAX7-FOXO1 fusion proteins function as drivers of oncogenesis by dysregulating multiple crucial cellular pathways. […] The fusion proteins drive the expression of other transcription factors such as MYCN and MYOD1, contributing to the RMS formation and progression. […] Moreover, the fusion proteins drive the expression of receptor tyrosine kinases (RTKs). […] The overexpression or activation mutations of both genes encoding the RTKs or their downstream signaling effector genes are common in FP RMS. […] This includes FGFR4 (fibroblast growth factor receptor 4), whose activating mutations are present in 7% of FP RMS patients, triggering RAS and STAT signaling pathways that induce tumor growth. […] Activation of the Ras/Raf/MEK/ERK and JAK/STAT pathways can result in prevention of apoptosis through phosphorylation of Bim and Bad, which result in the loss of the ability to heterodimerize with survival proteins BCL-XL and BCL-2.

• #13 New insights into signalling-pathway alterations in rhabdomyosarcoma | British Journal of Cancer

  https://www.nature.com/articles/bjc2014471

  The MEK/ERK signalling pathway contributes to the activation of p21 expression in RMS cells and is correlated with growth arrest and differentiation of RD cells. […] TBX2 is also associated with two well-known cancer modifiers, the retinoblastoma tumour suppressor protein (pRB) and the Myc family. […] TBX2 mediates repression by binding the HDAC1, which serves to target HDAC1 to promoters and it was found that TBX2 recruits HDAC1 to target promoters, including p21, in RMS cells as well. […] The identification of new protein factors, which mediate cell growth in RMS, such as TBX2, may connect the deregulation of the PI3K pathway with histone deacetylation of the genes encoding pivotal cell-cycle regulators such as p21.

• #14 Genetic Characterization, Current Model Systems and Prognostic Stratification in PAX Fusion-Negative vs. PAX Fusion-Positive Rhabdomyosarcoma

  https://www.mdpi.com/2073-4425/12/10/1500

  Importantly, RMS can occur at sites that lack skeletal muscle, such as the salivary gland, gallbladder, and bladder, which places a true skeletal, muscle-derived origin into question. […] The Sonic hedgehog (SHH) pathway is critical in early stages of skeletal muscle development, and many studies have shown its importance in ERMS pathogenesis. […] Several FN-RMS models have shown to be associated with aberrant SHH signaling. […] Another important gene in embryonic and postnatal skeletal myogenesis is NOTCH1. […] The third important player in embryonic signaling pathways affecting skeletal muscle development is WNT. […] More recently, the MAPK pathway in RAS-driven FN-RMS was shown to promote RMS pathogenesis while inhibiting MYOG expression. […] The mTOR pathway seems to contribute to RMS invasion, while inhibition of it seems to diminish cellular migration, invasion and angiogenesis in RMS models. […] Within the last few decades, significant progress has been made regarding the understanding of myogenesis and, thus, what may underlie the pathogenesis of RMS.

• #15 Laryngeal embryonal rhabdomyosarcoma in an adult – A case presentation in the eyes of geneticists and clinicians | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-166

  Multiple signaling pathways seem to be involved in ERMS development and progression. […] Moreover the pathogenesis of ERMS was also linked to deregulation of the hedgehog signaling pathway. […] Recent findings suggest that haploinsufficiency for the two tumor suppressor genes PTCH (patched (Drosophila) homolog (nevoid basal cell carcinoma syndrome)) and SUFU (suppressor of fused homolog)-which are both active in this signaling pathway-is frequent in ERMS development. […] In the majority of ERMS cases screened, overexpression of MCL1 (induced myeloid leukemia cell differentiation protein) and MAP2K4 (mitogen-activated protein kinase 4) genes, both involved in cell viability regulation, was reported. […] At the same time a few studies performed on series of embryonal tumors suggest that dysregulation of RAS function may be relevant to ERMS disease pathogenesis.

• #16 Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies

  https://www.mdpi.com/2072-6694/15/21/5269

  Additionally, the overexpression of FGFR4 tyrosine kinase in RMS cell lines induces its auto-phosphorylation and constitutive signaling that result in the prevention of apoptosis by targeting the IGF1R-PI3K-mTOR (insulin growth factor 1 receptor/phosphoinositide 3-kinase/mammalian target of rapamycin) pathway. […] An increasing body of evidence suggests that epigenetic regulation contributes to RMS development and progression. […] The identification of PAX-FKHR fusion genes has shifted our research focus with the goal of elucidating pathways that lead not only to the chromosomal translocations, but also on how these oncogenic fusion proteins alter the cell phenotype and can be exploited pharmacologically. […] This approach could allow for the identification of biomarkers that could be applied to individualize the targeted therapy and improve RMS prognosis.

• #17 Rhabdomyosarcoma | Cancer Genetics Web

  http://www.cancerindex.org/geneweb/X2002.htm

  The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). […] PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. […] Rhabdomyosarcoma is an aggressive solid tumor that may disseminate hematogenously giving metastasis which represents the most important prognostic factor. […] Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. […] The chromosomal translocation that leads to alveolar rhabdomyosarcoma development generates a novel TAD that is likely to favour ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories.

• #18 Clonality and Evolutionary History of Rhabdomyosarcoma | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005075

  To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. […] Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. […] Our findings provide information critical to the understanding of tumorigenesis of RMS. […] In PFN-RMS, genomic loss of heterozygosity on chromosome 11p15.5 and non-synonymous mutations in RAS pathway and cell cycle genes (FGFR4, KRAS, NRAS, HRAS and CCDN1), as well as several genes not previously known to be drivers of RMS, including PKN1, CUL2, and TTK, occurs early in the evolutionary history of tumor;

• #19 CD73 contributes to the pathogenesis of fusion-negative rhabdomyosarcoma through the purinergic signaling pathway – ADS

  https://ui.adsabs.harvard.edu/abs/2024PNAS..12115925H/abstract

  Fusion-negative rhabdomyosarcoma (FN-RMS) accounts for more than 80% of all rhabdomyosarcoma cases. However, the mechanisms driving FN-RMS remain poorly understood, resulting in limited therapeutic strategies. […] We identified CD73, a cell membrane 5′ ectonucleotidase, as a TWIST2 regulated gene contributing to the pathogenesis of FN-RMS. […] We show that knockdown of CD73 decreased FN-RMS pathogenic growth in vitro and in vivo. Moreover, CD73 knockdown induced cell cycle arrest and decreased migration while initiating the myogenic program in FN-RMS cells. […] We also showed that the role of CD73 in FN-RMS is mediated by its enzymatic activity and the activation of the purinergic signaling pathway. Our results warrant consideration of CD73 as a potential therapeutic target in FN-RMS.

• #20

  https://grantome.com/grant/NIH/ZIA-BC010871-05

  Multiple functional in vivo studies confirmed that the cytoskeletal linker EZRIN and the homeodomain-containing transcription factor SIX1 both have essential roles in determining the metastatic fate of rhabdomyosarcoma cells. […] Notably, EZRIN and SIX1 expression levels were also both enhanced in human rhabdomyosarcoma tissue samples, significantly correlating with clinical stage. […] Remarkably, subsequent molecular analyses showed that the EZRIN gene was in fact a direct transcriptional target of SIX1, and indispensable for SIX1-mediated rhabdomyosarcoma metastasis. […] Recently, we have found that SIX1 regulates EZRIN expression, at least in part, through epigenetic modification of the chromatin around the EZRIN gene locus, including regulating the states of methylation and acetylation within the histone tails. […] These findings support the potential therapeutic targeting of FGFR4 in RMS.

• #21 Soft Tissues: Rhabdomyosarcoma

  https://atlasgeneticsoncology.org/solid-tumor/5004/soft-tissues-rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) refers to a family of mesenchymal tumours related to the skeletal muscle lineage. […] RMS is postulated to be derived from mesodermal tissues. […] Studies of cytogenetics and other acquired genetic changes in ERMS and ARMS have revealed significant genetic differences between these two subtypes. […] Most ARMS cases are distinguished from ERMS and other solid tumors by the presence of one of two recurrent chromosomal translocations, which generate related fusion genes. […] ERMS does not have recurrent structural chromosome rearrangements, but rather has frequent chromosome gains and losses. […] Most cases of RMS occur sporadically without an apparent genetic predisposition. However, a small subset of RMS is associated with the following known genetic syndromes: Hereditary retinoblastoma syndrome (RB1), Li-Fraumeni syndrome (TP53), Neurofibromatosis type I (NF1), Costello syndrome (HRAS), Beckwith-Wiedemann syndrome (11p15 genes), Nevoid basal cell carcinoma syndrome (PTCH), Rubinstein-Taybi syndrome (CREBBP). […] Molecular pathogenesis of rhabdomyosarcoma.

• #22 What Causes Rhabdomyosarcoma?| Causes of Rhabdomyosarcoma | American Cancer Society

  https://www.cancer.org/cancer/types/rhabdomyosarcoma/causes-risks-prevention/what-causes.html

  The cause of most cases of rhabdomyosarcoma (RMS) is not well understood, and there are very few known risk factors for this type of cancer. […] Researchers are learning how normal cells become cancerous because of certain changes in their DNA. […] Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. […] A small portion of people with RMS have inherited gene changes from a parent that put them at higher risk. […] For example, people with Li-Fraumeni syndrome have changes in the TP53 tumor suppressor gene, which cause it to make a defective p53 protein. […] When p53 is not working, cells with DNA damage keep dividing, which can lead to further defects in other genes, and eventually cancer. […] Certain genes in a cell can be turned on when bits of DNA are switched from one chromosome to another.

• #23 Rhabdomyosarcoma: Symptoms, Prognosis & Treatment

  https://my.clevelandclinic.org/health/diseases/6226-rhabdomyosarcoma

  Rhabdomyosarcoma happens when immature muscle cells mutate, becoming cancerous cells that multiply and create tumors. Certain genetic mutations, including a change that creates the fusion gene PAX/FOX01, may cause a type of rhabdomyosarcoma. People with certain inherited disorders have an increased risk of developing the condition: […] Rhabdomyosarcoma is a rare type of cancer known as soft tissue sarcoma. It develops in your skeletal muscles. […] There are different types of rhabdomyosarcomas, some of which are aggressive and more difficult to treat. […] Rhabdomyosarcoma symptoms may resemble less serious conditions. Many health issues can cause symptoms like nosebleeds, vomiting or lumps and bumps and may not be symptoms of rhabdomyosarcoma. […] Risk group classifications are low risk, intermediate risk and high risk. Your child’s oncology team uses risk group classification to plan treatment, assess the chance the tumor will come back after treatment and establish a prognosis, or what you can expect to happen after treatment.

• #24 Rhabdomyosarcoma in adolescent and young adult patients: current persp | AHMT

  https://www.dovepress.com/rhabdomyosarcoma-in-adolescent-and-young-adult-patients-current-perspe-peer-reviewed-fulltext-article-AHMT

  Rhabdomyosarcoma (RMS), a malignant tumor of mesenchymal origin, is the third most common extracranial malignant solid tumor in children and adolescents. […] Advances in the research of the embryonal and alveolar variants have improved our understanding of certain genes and biologic pathways that are involved in RMS, but much less is known for the other variants. […] The development of experimental animal models has significantly contributed to our current understanding of the molecular factors that play a role in RMS genesis. […] Studies derived from these models have shown chemical and physical (heavy metals, ionizing radiation, polycyclic aromatic hydrocarbons), but also biological (viral proteins, p53 pathway alterations, rat sarcoma [RAS] or hepatocyte growth factor alterations) triggers of RMS.

• #25

  https://www.omim.org/entry/268220

  Sharp et al. (2002) showed that simultaneous loss of Ink4a/Arf (600160) function and disruption of Met (164860) signaling in Ink4a/Arf -/- mice transgenic for hepatocyte growth factor/scatter factor (Hgf/Sf; 142409) induces rhabdomyosarcoma with extremely high penetrance and short latency. […] Sharp et al. (2002) concluded that human MET and INK4A/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in rhabdomyosarcoma pathogenesis. […] The marked synergism in mice between aberrant MET signaling and INK4A/ARF inactivation, lesions individually implicated in human rhabdomyosarcoma, suggested a therapeutic combination to combat this devastating childhood cancer.

• #26

  https://omim.org/entry/268220

  Sharp et al. (2002) showed that simultaneous loss of Ink4a/Arf (600160) function and disruption of Met (164860) signaling in Ink4a/Arf -/- mice transgenic for hepatocyte growth factor/scatter factor (Hgf/Sf; 142409) induces rhabdomyosarcoma with extremely high penetrance and short latency. […] In cultured myoblasts, Met activation and Ink4a/Arf loss suppressed myogenesis in an additive fashion. […] Sharp et al. (2002) concluded that human MET and INK4A/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in rhabdomyosarcoma pathogenesis. […] The marked synergism in mice between aberrant MET signaling and INK4A/ARF inactivation, lesions individually implicated in human rhabdomyosarcoma, suggested a therapeutic combination to combat this devastating childhood cancer.

• #27 Rhabdomyosarcoma in adolescent and young adult patients: current persp | AHMT

  https://www.dovepress.com/rhabdomyosarcoma-in-adolescent-and-young-adult-patients-current-perspe-peer-reviewed-fulltext-article-AHMT

  Pleomorphic RMS is more common in adults compared to children. […] One animal study was able to demonstrate the development of the pleomorphic RMS tumors in p53-deficient mice when KRAS was overexpressed. […] Another study suggested that ERMS and the undifferentiated pleomorphic sarcoma form a continuum, with mutant p53, Ptch1, or Rb1 in satellite cells, giving rise to undifferentiated sarcoma and ERMS originating from myoblasts that express satellite cells markers.

• #28 Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies

  https://www.mdpi.com/2072-6694/15/21/5269

  Rhabdomyosarcoma (RMS) is a pediatric soft tissue malignancy with poor survival rates for the high-risk and recurrent disease and has the potential for significant morbidity associated with treatment. […] Despite advances in diagnostic and treatment methods over the past few decades, children with high-risk RMS and recurrent disease have 5-year survival rates of less than 30% and 17%, respectively. […] Prognostic stratification is significant because 15–20% of children have diffused metastatic disease at the time of diagnosis. […] However, despite these developments, the cure rate for pediatric patients with metastatic or recurrent disease remains low and current RMS therapies continue to pose potential life-threatening toxicities, which can lead to lifelong morbidity. […] Over the last three decades, there have been several national and international clinical trials which have resulted in refined treatment regimens based on the tumor stage and clinical group, leading to improved pediatric RMS survival rates.

• #29 Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings | Boletín Médico del Hospital Infantil de México

  https://www.elsevier.es/en-revista-boletin-medico-del-hospital-infantil-401-articulo-alveolar-rhabdomyosarcoma-origin-prognostic-implications-S1665114616301289

  The prognosis of patients with RMS depends on the grade of the tumor, age, type of resection, histology, presence of the mentioned translocations and number of sites with metastases. […] The epithelial-mesenchyme transition (EMT) is an important event for the invasion and metastasis of the tumor, and it is associated with a poor prognosis and with chemoresistance. […] Chemoresistance is one of the main problems in almost all types of cancer. Despite the fact that there is an improvement in the chemotherapeutic agents, many patients with cancer die because they develop chemoresistance.

• #30

  https://aacr.figshare.com/collections/Data_from_Oncogenic_NRAS_Required_for_Pathogenesis_of_Embryonic_Rhabdomyosarcoma_Relies_upon_the_HMGA2_IGF2BP2_Pathway/6504435

  Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. […] Mechanistic investigations revealed that upregulation of the insulinlike growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. […] Taken together, these findings implicate the HMGA2IGFBP2NRAS signaling pathway as a critical oncogenic driver in ERMS.

• #31 Pannexin 1 inhibits rhabdomyosarcoma progression through a mechanism independent of its canonical channel function | Oncogenesis

  https://www.nature.com/articles/s41389-018-0100-4

  Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma of childhood thought to arise from impaired differentiation of skeletal muscle progenitors. […] We have recently identified Pannexin 1 (PANX1) channels as a novel regulator of skeletal myogenesis. […] PANX1 transcript and protein levels are down-regulated in embryonal (eRMS) and alveolar RMS (aRMS) patient-derived cell lines and primary tumor specimens as compared to differentiated skeletal muscle myoblasts and tissue, respectively. […] Ectopic expression of PANX1 in eRMS (Rh18) and aRMS (Rh30) cells significantly decreased their proliferative and migratory potential. […] Ectopic PANX1 abolished 3D spheroid formation in eRMS and aRMS cells and induced regression of established spheroids through induction of apoptosis. […] PANX1 expression also significantly reduced the growth of human eRMS and aRMS tumor xenografts in vivo.

• #32 Pannexin 1 inhibits rhabdomyosarcoma progression through a mechanism independent of its canonical channel function | Oncogenesis

  https://www.nature.com/articles/s41389-018-0100-4

  PANX1 does not form active channels when expressed in eRMS (Rh18) and aRMS (Rh30) cells and the addition of PANX1 channel inhibitors did not alter or reverse the PANX1-mediated reduction of cell proliferation and migration. […] Altogether our findings suggest that PANX1 alleviates RMS malignant properties in vitro and in vivo through a process that is independent of its canonical channel function. […] Our findings that PANX1 transcript and protein levels in RMS cells were comparable to that of proliferative and undifferentiated skeletal muscle myoblasts suggested that the down-regulation of PANX1 may be involved in the malignant phenotype of RMS. […] Importantly, this effect was consistent between eRMS and aRMS despite their heterogeneous background of genetic alterations. […] Collectively, these complementary approaches suggest that PANX1 tumor suppressive function in RMS involves a mechanism independent of its canonical channel activity.

• #33 Alveolar rhabdomyosarcoma – The molecular drivers of PAX3/7-FOXO1-induced tumorigenesis | Skeletal Muscle | Full Text

  https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-2-25

  The PAX3-FOXO1 fusion protein can be detected in about 55% of ARMS cases. […] During normal development, PAX3 expression occurs in the neural tube and dermomyotome, and it is required for the normal migration of skeletal muscle precursors to the limb bud. […] Expression of these ARMS fusion transcription factors is thought to abrogate normal skeletal muscle differentiation, allowing aberrant cell division and tumor development. […] PAX3-FOXO1 is capable of suppressing MyoD expression and activity. […] The remaining ARMS tumors are classed as fusion-negative ARMS. However, fusion-negative ARMS are indistinguishable on the levels of gene expression and in clinical outcome from ERMS tumors, leading some to argue that translocation status should be the defining factor of ARMS. […] Within the ARMS subtype, prognosis can vary by disease stage at diagnosis as well as translocation status.

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