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BACKGROUND: EWSR1::NFATC2 rearranged sarcomas are a group of rare round, undifferentiated sarcomas with clinicopathological features different from those of Ewing's sarcoma (ES) family and other non-ES sarcomas. We report 4 cases of this rare sarcoma and review their features. MATERIALS AND METHODS: Four cases of EWSR1::NFATC2 rearranged round cell sarcoma of the bone from the Pathology Department of Peking University People's Hospital were retrospectively studied. Clinical and pathological data were summarized, and immunohistochemical staining, fluorescence in situ hybridization (FISH), and Next-generation sequencing (NGS) were performed. Relevant literature reports were also reviewed. RESULTS: Among the four cases of EWSR1::NFATC2 rearranged round cell sarcoma, three were male, and one was female, with the age ranged from 14 to 34 years old at diagnosis (mean age: 27.5 years). All tumors were located in the femur and ranged in size from 4 to 8cm (mean 6cm), involving the surrounding soft tissues. All four patients underwent surgical treatment, and three received chemotherapy and radiotherapy postoperatively. Follow-up results showed that all four patients were alive. Histologically, the tumors exhibited small round cell sarcoma phenotype, with the stroma rich in mucin or exhibiting a glassy appearance. The tumor cells diffusely expressed CD99, NKX2.2, NKX3.1 and focal expression of CK and EMA was observed. FISH analysis showed that EWSR1 gene rearrangement was detected in all 4 cases, accompanied by 5' locus amplification. EWSR1::NFATC2 fusion probe demonstrated multi yellow fusion signals. NGS identified EWSR1::NFATC2 breakpoints in exon 9 and exon 3 in all 4 cases. The average follow-up duration of the study group was 88 months (range from 26-180 months). One case experienced both local recurrence and metastasis to the lung and chest wall. One case presented with local recurrence. The remaining two cases did not have the recurrence or metastasis. CONCLUSION: Although the disease can locally recur and metastasize to the lungs, its mortality rate is significantly lower than that of Ewing sarcoma and other high-grade small round cell undifferentiated sarcomas. Therefore, it supports to classify this tumor as a separate subtype of small round cell sarcoma.
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Tumores Neuroectodérmicos Periféricos Primitivos , Proteínas de Fusión Oncogénica , Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Exones , Hibridación Fluorescente in Situ , Factores de Transcripción NFATC/genética , Estudios Retrospectivos , Proteína EWS de Unión a ARN/genéticaRESUMEN
In order to improve the real-time performance of the trajectory tracking of autonomous vehicles, this paper applies the alternating direction multiplier method (ADMM) to the receding optimization of model predictive control (MPC), which improves the computational speed of the algorithm. Based on the vehicle dynamics model, the output equation of the autonomous vehicle trajectory tracking control system is constructed, and the auxiliary variable and the dual variable are introduced. The quadratic programming problem transformed from the MPC and the vehicle dynamics constraints are rewritten into the solution of the ADMM form, and a decreasing penalty factor is used during the solution process. The simulation verification is carried out through the joint simulation platform of Simulink and Carsim. The results show that, compared with the active set method (ASM) and the interior point method (IPM), the algorithm proposed in this paper can not only improve the accuracy of trajectory tracking, but also exhibits good real-time performance in different prediction time domains and control time domains. When the prediction time domain increases, the calculation time shows no significant difference. This verifies the effectiveness of the ADMM in improving the real-time performance of MPC.
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The FOS gene family has been implicated in tumourigenesis across several tumour types, particularly mesenchymal tumours. The rare fibrous tumour desmoplastic fibroblastoma is characterised by overexpression of FOSL1. However, previous studies using cytogenetic and molecular techniques did not identify an underlying somatic change involving the FOSL1 gene to explain this finding. Prompted by an unusual index case, we report the discovery of a novel FOSL1 rearrangement in desmoplastic fibroblastoma using whole-genome and targeted RNA sequencing. We investigated 15 desmoplastic fibroblastomas and 15 fibromas of tendon sheath using immunohistochemistry, in situ hybridisation and targeted RNA sequencing. Rearrangements in FOSL1 and FOS were identified in 10/15 and 2/15 desmoplastic fibroblastomas respectively, which mirrors the pattern of FOS rearrangements observed in benign bone and vascular tumours. Fibroma of tendon sheath, which shares histological features with desmoplastic fibroblastoma, harboured USP6 rearrangements in 9/15 cases and did not demonstrate rearrangements in any of the four FOS genes. The overall concordance between FOSL1 immunohistochemistry and RNA sequencing results was 90%. These findings illustrate that FOSL1 and FOS rearrangements are a recurrent event in desmoplastic fibroblastoma, establishing this finding as a useful diagnostic adjunct and expanding the spectrum of tumours driven by FOS gene family alterations. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Fibroma Desmoplásico , Fibroma , Neoplasias de los Tejidos Blandos , Humanos , Fibroma Desmoplásico/diagnóstico , Fibroma Desmoplásico/genética , Fibroma Desmoplásico/patología , Fibroma/genética , Reordenamiento Génico , Hibridación in Situ , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Ubiquitina Tiolesterasa/genéticaRESUMEN
BACKGROUND: Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations. METHODS: In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings. RESULTS: IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group. CONCLUSIONS: Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.
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Neoplasias Óseas , Condrosarcoma , Adulto , Anciano , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Condrosarcoma/genética , Condrosarcoma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Modelos Genéticos , Mutación , PronósticoRESUMEN
BACKGROUND: BCOR-CCNB3 sarcoma (BCS) is a group of undifferentiated small round cell sarcomas harboring the BCOR gene rearrangement which shares morphology with the Ewing sarcoma family as well as other malignant round blue cell tumors, thus making them difficult to diagnose. The aim of this study was to explore the role of molecular techniques in the diagnosis of BCS. METHODS: Twenty-three cases of EWSR1 rearrangement-negative undifferentiated small round cell sarcomas (Ewing-like sarcoma) were analyzed for the presence of BCOR gene rearrangement by Fluorescence in situ hybridization (FISH) and Reverse Transcription -Polymerase Chain Reaction (RT-PCR). The clinicopathological features of the positive cases were also reviewed. Fifteen additional cases were used as negative controls. RESULTS: Eight cases were found with BCOR gene rearrangement by FISH and reappraised as BCS. The patients ranged in age from 8 to 20 years old, with a male predominance (M:F = 6:2). All tumors were located in the lower extremities. The tumor locations were more common in bone (n = 6) than deep soft tissue (n = 2). Histologically, 7 of 8 tumors were predominately composed of spindle or ovoid cells. The tumor cells were usually arranged in solid hypercellular sheets without a distinct architectural pattern. IHC showed expression of TLE1 (100%), CCNB3 (88%), BCOR (71%). RT-PCR for BCOR-CCNB3 fusion transcript was positive in 7 of 8 cases. Pre-operative chemotherapy resulted in eradication of tumors in 5 patients after a follow-up of 7 to 42 months. CONCLUSIONS: Efficient diagnosis of BCOR rearranged sarcomas is achieved by the using a combination of FISH and RT-PCR assays.
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Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Reordenamiento Génico , Hibridación Fluorescente in Situ , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma de Ewing/genética , Adolescente , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Niño , Ciclina B/genética , Femenino , Fusión Génica , Humanos , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Sarcoma de Ewing/patología , Sarcoma de Ewing/terapia , Adulto JovenRESUMEN
Osteosarcoma, the most common primary malignant tumour of bone, affects both children and adults. No fundamental biological differences between paediatric and adult osteosarcoma are known. Here, we apply multi-region whole-genome sequencing to an index case of a 4-year-old child whose aggressive tumour harboured high-level, focal amplifications of MYC and CCNE1 connected by translocations. We reanalysed copy number readouts of 258 cases of high-grade osteosarcoma from three different cohorts and identified a significant enrichment of focal MYC, but not CCNE1, amplifications in children. Furthermore, we identified four additional cases of MYC and CCNE1 coamplification, highlighting a rare driver event which warrants further investigation. Our findings indicate that amplification of the MYC oncogene is a major driver of childhood osteosarcoma, while CCNE1 appears recurrently amplified independent of age.
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Envejecimiento/genética , Ciclina E/genética , Amplificación de Genes , Genes myc/genética , Proteínas Oncogénicas/genética , Osteosarcoma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteosarcoma/patologíaRESUMEN
Diagnosing bone and soft tissue neoplasms remains challenging because of the large number of subtypes, many of which lack diagnostic biomarkers. DNA methylation profiles have proven to be a reliable basis for the classification of brain tumours and, following this success, a DNA methylation-based sarcoma classification tool from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg has been developed. In this study, we assessed the performance of their classifier on DNA methylation profiles of an independent data set of 986 bone and soft tissue tumours and controls. We found that the 'DKFZ Sarcoma Classifier' was able to produce a diagnostic prediction for 55% of the 986 samples, with 83% of these predictions concordant with the histological diagnosis. On limiting the validation to the 820 cases with histological diagnoses for which the DKFZ Classifier was trained, 61% of cases received a prediction, and the histological diagnosis was concordant with the predicted methylation class in 88% of these cases, findings comparable to those reported in the DKFZ Classifier paper. The classifier performed best when diagnosing mesenchymal chondrosarcomas (CHSs, 88% sensitivity), chordomas (85% sensitivity), and fibrous dysplasia (83% sensitivity). Amongst the subtypes least often classified correctly were clear cell CHSs (14% sensitivity), malignant peripheral nerve sheath tumours (27% sensitivity), and pleomorphic liposarcomas (29% sensitivity). The classifier predictions resulted in revision of the histological diagnosis in six of our cases. We observed that, although a higher tumour purity resulted in a greater likelihood of a prediction being made, it did not correlate with classifier accuracy. Our results show that the DKFZ Classifier represents a powerful research tool for exploring the pathogenesis of sarcoma; with refinement, it has the potential to be a valuable diagnostic tool.
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Metilación de ADN/genética , Sarcoma/clasificación , Biomarcadores de Tumor , Neoplasias Óseas/clasificación , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Clasificación , Diagnóstico Diferencial , Perfilación de la Expresión Génica , Técnicas Genéticas , Humanos , Sarcoma/diagnóstico , Sarcoma/patología , Neoplasias de los Tejidos Blandos/clasificación , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Diagnosing MPNST can be challenging, but genetic alterations recently identified in polycomb repressive complex 2 (PRC2) core component genes, EED and SUZ12, resulting in global loss of the histone 3 lysine 27 trimethylation (H3K27me3) epigenetic mark, represent drivers of malignancy and a valuable diagnostic tool. However, the reported loss of H3K27me3 expression ranges from 35% to 84%. We show that advances in molecular pathology now allow many MPNST mimics to be classified confidently. We confirm that MPNSTs harbouring mutations in PRC2 core components are associated with loss of H3K27me3 expression; whole-genome doubling was detected in 68%, and SSTR2 was amplified in 32% of MPNSTs. We demonstrate that loss of H3K27me3 expression occurs overall in 38% of MPNSTs, but is lost in 76% of histologically classical cases, whereas loss was detected in only 23% cases with heterologous elements and 14% where the diagnosis could not be provided on morphology alone. H3K27me3 loss is rarely seen in other high-grade sarcomas and was not found to be associated with an inferior outcome in MPNST. We show that DNA methylation profiling distinguishes MPNST from its histological mimics, was unrelated to anatomical site, and formed two main clusters, MeGroups 4 and 5. MeGroup 4 represents classical MPNSTs lacking H3K27me3 expression in the majority of cases, whereas MeGroup 5 comprises MPNSTs exhibiting non-classical histology and expressing H3K27me3 and cluster with undifferentiated sarcomas. The two MeGroups are distinguished by differentially methylated PRC2-associated genes, the majority of which are hypermethylated in the promoter regions in MeGroup 4, indicating that the PRC2 target genes are not expressed in these tumours. The methylation profiles of MPNSTs with retention of H3K27me3 in MeGroups 4 and 5 are independent of mutations in PRC2 core components and the driver(s) in these groups remain to be identified. Our results open new avenues of investigation. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Histonas/metabolismo , Neurofibrosarcoma/diagnóstico , Neurofibrosarcoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neurofibrosarcoma/clasificación , Adulto JovenRESUMEN
The largest whole genome sequencing (WGS) endeavour involving cancer and rare diseases was initiated in the UK in 2015 and ran for 5 years. Despite its rarity, sarcoma ranked third overall among the number of patients' samples sent for sequencing. Herein, we recount the lessons learned by a specialist sarcoma centre that recruited close to 1000 patients to the project, so that we and others may learn from our experience. WGS data was generated from 597 patients, but samples from the remaining approximately 400 patients were not sequenced. This was largely accounted for by unsuitability due to extensive necrosis, secondary to neoadjuvant radiotherapy or chemotherapy, or being placed in formalin. The number of informative genomes produced was reduced further by a PCR amplification step. We showed that this loss of genomic data could be mitigated by sequencing whole genomes from needle core biopsies. Storage of resection specimens at 4 °C for up to 96 h overcame the challenge of freezing tissue out of hours including weekends. Removing access to formalin increased compliance to these storage arrangements. With over 70 different sarcoma subtypes described, WGS was a useful tool for refining diagnoses and identifying novel alterations. Genomes from 350 of the cohort of 597 patients were analysed in this study. Overall, diagnoses were modified for 3% of patients following review of the WGS findings. Continued refinement of the variant-calling bioinformatic pipelines is required as not all alterations were identified when validated against histology and standard of care diagnostic tests. Further research is necessary to evaluate the impact of germline mutations in patients with sarcoma, and sarcomas with evidence of hypermutation. Despite 50% of the WGS exhibiting domain 1 alterations, the number of patients with sarcoma who were eligible for clinical trials remains small, highlighting the need to revaluate clinical trial design.
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Biomarcadores de Tumor/genética , Mutación , Sarcoma/genética , Secuenciación Completa del Genoma , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Medicina de Precisión , Valor Predictivo de las Pruebas , Pronóstico , Proyectos de Investigación , Sarcoma/mortalidad , Sarcoma/patología , Sarcoma/terapia , Adulto JovenRESUMEN
The expression of p16/CDKN2A, the second most commonly inactivated tumour suppressor gene in cancer, is lost in the majority of chordomas. However, the mechanism(s) leading to its inactivation and contribution to disease progression have only been partially addressed using small patient cohorts. We studied 384 chordoma samples from 320 patients by immunohistochemistry and found that p16 protein was lost in 53% of chordomas and was heterogeneously expressed in these tumours. To determine if CDKN2A copy number loss could explain the absence of p16 protein expression we performed fluorescence in situ hybridisation (FISH) for CDKN2A on consecutive tissue sections. CDKN2A copy number status was altered in 168 of 274 (61%) of samples and copy number loss was the most frequent alteration acquired during clinical disease progression. CDKN2A homozygous deletion was always associated with p16 protein loss but only accounted for 33% of the p16-negative cases. The remaining immunonegative cases were associated with disomy (27%), monosomy (12%), heterozygous loss (20%) and copy number gain (7%) of CDKN2A, supporting the hypothesis that loss of protein expression might be achieved via epigenetic or post-transcriptional regulatory mechanisms. We identified that mRNA levels were comparable in tumours with and without p16 protein expression, but other events including DNA promoter hypermethylation, copy number neutral loss of heterozygosity and expression of candidate microRNAs previously implicated in the regulation of CDKN2A expression were not identified to explain the protein loss. The data argue that p16 loss in chordoma is commonly caused by a post-transcriptional regulatory mechanism that is yet to be defined.
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Cordoma/genética , Cordoma/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Genes p16/fisiología , Adolescente , Adulto , Anciano , Niño , Cordoma/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Eliminación de Gen , Humanos , Inmunohistoquímica/métodos , Pérdida de Heterocigocidad/genética , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Adulto JovenRESUMEN
Osteoblastoma and osteoid osteoma together are the most frequent benign bone-forming tumor, arbitrarily separated by size. In some instances, it can be difficult to differentiate osteoblastoma from osteosarcoma. Following our recent description of FOS gene rearrangement in these tumors, the aim of this study is to evaluate the value of immunohistochemistry in osteoid osteoma, osteoblastoma, and osteosarcoma for diagnostic purposes. A total of 337 cases were tested with antibodies against c-FOS: 84 osteoblastomas, 33 osteoid osteomas, 215 osteosarcomas, and 5 samples of reactive new bone formation. In all, 83% of osteoblastomas and 73% of osteoid osteoma showed significant expression of c-FOS in the osteoblastic tumor cell component. Of the osteosarcomas, 14% showed c-FOS expression, usually focal, and in areas with severe morphologic atypia which were unequivocally malignant: 4% showed more conspicuous expression, but these were negative for FOS gene rearrangement. We conclude that c-FOS immunoreactivity is present in the vast majority of osteoblastoma/osteoid osteoma, whereas its expression is usually focal or patchy, in no more than 14% of osteosarcoma biopsies. Therefore, any bone-forming tumor cases with worrying histologic features would benefit from fluorescence in situ hybridization analysis for FOS gene rearrangement. Our findings highlight the importance of undertaking a thorough assessment of expression patterns of antibodies in the light of morphologic, clinical, and radiologic features.
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Biomarcadores de Tumor/análisis , Neoplasias Óseas/química , Osteoblastoma/química , Osteoma Osteoide/química , Proteínas Proto-Oncogénicas c-fos/análisis , Adolescente , Adulto , Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Niño , Preescolar , Diagnóstico Diferencial , Inglaterra , Femenino , Reordenamiento Génico , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Osteoblastoma/genética , Osteoblastoma/patología , Osteoma Osteoide/genética , Osteoma Osteoide/patología , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas c-fos/genética , Suiza , Adulto JovenRESUMEN
A fusion between fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) has been reported previously in isolated cases of the synovial chondromatosis. To analyze further and validate the findings, we performed FISH and demonstrated recurrent FN1-ACVR2A rearrangements in synovial chondromatosis (57%), and chondrosarcoma secondary to synovial chondromatosis (75%), showing that FN1 and/or AVCR2A gene rearrangements do not distinguish between benign and malignant synovial chondromatosis. RNA sequencing revealed the presence of the FN1-ACVR2A fusion in several cases that were negative by FISH suggesting that the true prevalence of this fusion is potentially higher than 57%. In soft tissue chondromas, FN1 alterations were detected by FISH in 50% of cases but no ACVR2A alterations were identified. RNA sequencing identified a fusion involving FN1 and fibroblast growth factor receptor 2 (FGFR2) in the case of soft tissue chondroma and FISH confirmed recurrent involvement of both FGFR1 and FGFR2. These fusions were present in a subset of soft tissue chondromas characterized by grungy calcification, a feature reminiscent of phosphaturic mesenchymal tumor. However, unlike the latter, fibroblast growth factor 23 (FGF23) mRNA expression was not elevated in soft tissue chondromas harboring the FN1-FGFR1 fusion. The mutual exclusivity of ACVR2A rearrangements observed in synovial chondromatosis and FGFR1/2 in soft tissue chondromas suggests these represent separate entities. There have been no reports of malignant soft tissue chondromas, therefore differentiating these lesions will potentially alter clinical management by allowing soft tissue chondromas to be managed more conservatively.
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Receptores de Activinas Tipo II/genética , Condroma/genética , Condromatosis Sinovial/genética , Fibronectinas/genética , Neoplasias de los Tejidos Blandos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Factor-23 de Crecimiento de Fibroblastos , Reordenamiento Génico , Humanos , Masculino , Persona de Mediana Edad , Fusión de Oncogenes , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto JovenRESUMEN
Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.
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Metilación de ADN , Perfilación de la Expresión Génica/métodos , Sarcoma/genética , Análisis de Secuencia de ADN/métodos , Evolución Molecular , Duplicación de Gen , Humanos , Mutación , Ploidias , PronósticoRESUMEN
The transcription factor FOS has long been implicated in the pathogenesis of bone tumours, following the discovery that the viral homologue, v-fos, caused osteosarcoma in laboratory mice. However, mutations of FOS have not been found in human bone-forming tumours. Here, we report recurrent rearrangement of FOS and its paralogue, FOSB, in the most common benign tumours of bone, osteoblastoma and osteoid osteoma. Combining whole-genome DNA and RNA sequences, we find rearrangement of FOS in five tumours and of FOSB in one tumour. Extending our findings into a cohort of 55 cases, using FISH and immunohistochemistry, provide evidence of ubiquitous mutation of FOS or FOSB in osteoblastoma and osteoid osteoma. Overall, our findings reveal a human bone tumour defined by mutations of FOS and FOSB.
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Neoplasias Óseas/genética , Osteoblastoma/genética , Proteínas Proto-Oncogénicas c-fos/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/metabolismo , Niño , Preescolar , Femenino , Reordenamiento Génico , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mutación , Osteoblastoma/diagnóstico , Osteoblastoma/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Secuenciación Completa del Genoma/métodos , Adulto JovenRESUMEN
Nasopharyngeal carcinoma (NPC) is an EBV associated carcinoma showing prevalence in southeast China. Distant metastasis is the major cause of death. Herein, we investigated the expressions of microRNA-3182 (miR-3182) and EBV-miR-BART8-3p in 89 cases of NPC and evaluated their correlation with clinical outcomes. Fifty-one percent of NPC showed high level expression of miR-3182. Its expression was significantly correlated with distant metastasis (P=0.005). Fifty-two percent of NPC demonstrated high level expression of EBV-miR-BART8-3p and its expression was significantly correlated with distant metastasis (P=0.006). The overall survival was influenced by the expression of miR-3182 and EBV-miR-BART8-3p. The patients with a high-level expression of miR-3182 and EBV-miR-BART8-3p had worse overall survival (P=0.005 and P=0.007). Multivariable analysis demonstrated that EBV-miR-BART8-3p was an independent prognostic factor for overall survival (P=0.018). The expression of miR-3182 was significantly correlated with EBV-miR-BART8-3p (P=0.045). In conclusion, this is the first study examining the potential clinical utility of miR-3182 and EBV-miR-BART8-3p as prognostic biomarkers in NPC. EBV infection may promote NPC progression by disrupting the expression of miR-3182.
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BACKGROUND: The most prevalent form of bone cancer is osteosarcoma (OS), which is associated with poor prognosis in case of metastases formation. Mice harbouring liver kinase B1 (LKB1+/-) develop osteoblastoma-like tumours. Therefore, we asked whether loss of LKB1 gene has a role in the pathogenesis of human OS. METHODS: Osteosarcomas (n=259) were screened for LKB1 and sirtuin 1 (SIRT1) protein expression using immunohistochemistry and western blot. Those cases were also screened for LKB1 genetic alterations by next-generation sequencing, Sanger sequencing, restriction fragment length polymorphism and fluorescence in situ hybridisation approaches. We studied LKB1 protein degradation through SIRT1 expression. MicroRNA expression investigations were also conducted to identify the microRNAs involved in the SIRT1/LKB1 pathway. RESULTS: Forty-one per cent (106 out of 259) OS had lost LKB1 protein expression with no evident genetic anomalies. We obtained evidence that SIRT1 impairs LKB1 protein stability, and that SIRT1 depletion leads to accumulation of LKB1 in OS cell lines resulting in growth arrest. Further investigations revealed the role of miR-204 in the regulation of SIRT1 expression, which impairs LKB1 stability. CONCLUSIONS: We demonstrated the involvement of sequential regulation of miR-204/SIRT1/LKB1 in OS cases and showed a mechanism for the loss of expression of LKB1 tumour suppressor in this malignancy.
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Neoplasias Óseas/genética , Osteosarcoma/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/metabolismo , Sirtuina 1/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Anoicis/genética , Antineoplásicos/farmacología , Benzamidas/farmacología , Neoplasias Óseas/metabolismo , Bortezomib/farmacología , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Humanos , MicroARNs/genética , Naftoles/farmacología , Osteosarcoma/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Transducción de Señal , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Serina-Treonina Quinasas TOR/metabolismo , TransfecciónRESUMEN
Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.
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Reordenamiento Génico , Mutación , Osteosarcoma/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Osteosarcoma/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
Giant cell tumor of bone (GCTB) is a locally aggressive subarticular tumor. Having recently reported that H3.3 G34W mutations are characteristic of this tumor type, we have now investigated the sensitivity and specificity of the anti-histone H3.3 G34W rabbit monoclonal antibody in a wide variety of tumors including histologic mimics of GCTB to assess its value as a diagnostic marker. We also determined the incidence of H3.3 G34 mutations in primary malignant bone tumors as assessed by genotype and H3.3 G34W immunostaining. A total of 3163 tumors were tested. Totally, 213/235 GCTB (90.6%) showed nuclear H3.3 p.G34W immunoreactivity. This was not the case for the rare variants, p.G34L, M, and V, which occurred most commonly in the small bones of the hands, patella, and the axial skeleton. If these sites were excluded from the analysis, H3.3 G34W expression was found in 97.8% of GCTB. Malignant bone tumors initially classified as osteosarcomas were the only other lesions (n=11) that showed G34W expression. Notably an additional 2 previously reported osteosarcomas with a p.G34R mutation were not immunoreactive for the antibody. A total of 11/13 of these malignant H3.3-mutant tumors exhibited an osteoclast-rich component: when imaging was available all but one presented at a subarticular site. We propose that subarticular primary malignant bone sarcoma with H3.3 mutations represent true malignant GCTB, even in the absence of a benign GCTB component.
Asunto(s)
Neoplasias Óseas/genética , Neoplasias Óseas/patología , Tumor Óseo de Células Gigantes/genética , Tumor Óseo de Células Gigantes/patología , Histonas/genética , Mutación , Adolescente , Biomarcadores de Tumor/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Reproducibilidad de los ResultadosRESUMEN
Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Antineoplásicos/farmacología , Cordoma/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/farmacología , Quinazolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cordoma/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Gefitinib , Humanos , Ratones , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Primary indeterminate dendritic cell tumor (IDCT) is an extremely neoplastic dendritic cell disorder. Little is known about its pathogenesis, etiology, and prognostic factors because of its rarity. Herein, we present a case report of a skin IDCT that arose in mosquito bite and discuss the correlation between hypersensitivity to mosquito bites and leukemia/lymphoma.A 28-year old man presented with multiple widespread cutaneous plaques and nodules 8 months after being bitten by a mosquito on his back. Dermatological examination revealed multiple skin-colored, well-demarcated plaques and nodules measuring approximately 0.5 to 1.8âcm in diameter all over the body. A biopsy of the skin lesion was taken. Morphologically, the dermis was effaced by round or polygonal cells with oval nuclei and abundant eosinophilic cytoplasm, arranged in nests and in some areas in a sheet-like pattern. The tumor cells were positive for CD68, CD1a, and S-100, whereas negative for Langerin and lack Birbeck granules ultrastructurally. A diagnosis of IDCT was made. No treatment was given. The patient was alive with spontaneous disease regression after 17 months of follow-up.IDCT is an extremely rare disease and may be associated with mosquito bite.