RESUMEN
Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1+/- ;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/- ;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.
Asunto(s)
Neoplasias Cerebelosas/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/genética , Proteínas del Grupo Polycomb/metabolismo , Proteínas Represoras/genética , Animales , Carcinogénesis/genética , Modelos Animales de Enfermedad , Proteínas Hedgehog/genética , Humanos , Ratones , Mutación , Receptor Patched-1/genética , Proteínas del Grupo Polycomb/genética , Proteínas Represoras/metabolismo , Eliminación de SecuenciaRESUMEN
In myeloid neoplasms, both fusion genes and gene mutations are well-established events identifying clinicopathological entities. In this study, we present a thus far undescribed t(X;21)(p11.4;q22.12) in five cases with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The translocation was isolated or accompanied by additional changes. It did not generate any fusion gene or gene deregulation by aberrant juxtaposition with regulatory sequences. Molecular analysis by targeted next-generation sequencing showed that the translocation was accompanied by at least one somatic mutation in TET2, EZH2, RUNX1, ASXL1, SRSF2, ZRSR2, DNMT3A, and NRAS genes. Co-occurrence of deletion of RUNX1 in 21q22 and of BCOR in Xp11 was associated with t(X;21). BCOR haploinsufficiency corresponded to a significant hypo-expression in t(X;21) cases, compared to normal controls and to normal karyotype AML. By contrast, RUNX1 expression was not altered, suggesting a compensatory effect by the remaining allele. Whole transcriptome analysis showed that overexpression of HOXA9 differentiated t(X;21) from both controls and t(8;21)-positive AML. In conclusion, we characterized a new recurrent reciprocal t(X;21)(p11.4;q22.12) chromosome translocation in MDS and AML, generating simultaneous BCOR and RUNX1 deletions rather than a fusion gene at the genomic level.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Síndromes Mielodisplásicos , Proteínas Proto-Oncogénicas , Proteínas Represoras , Translocación Genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cromosomas Humanos Par 21/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genéticaRESUMEN
We present two cases of malignant ossifying fibromyxoid tumor (OFMT) which eluded diagnosis due to compelling clinicopathologic mimicry, compounded by similarly elusive underlying molecular drivers. The first is of a clavicle mass in a 69 year-old female, which histologically showed an infiltrative nested and trabeculated proliferation of monomorphic cells giving rise to scattered spicules of immature woven bone. Excepting SATB2 positivity, the lesion showed an inconclusive immunoprofile which along with negative PHF1 FISH led to an initial diagnosis of high-grade osteosarcoma. Next generation sequencing (NGS) revealed a particularly rare CREBBP::BCORL1 fusion. The second illustrates the peculiar presentation of a dural-based mass in a 52 year-old female who presented with neurologic dyscrasias. Sections showed a sheeted monotonous proliferation of ovoid to spindle cells, but in contrast to Case #1, the tumor contained an exuberance of reticular osteoid and woven bone deposition mimicking malignant osteogenic differentiation. NGS showed a novel CREBZF::PHF1 fusion. Both tumors recurred locally less than 1 year post-operatively. As such we reiterate that careful morphologic examination is axiomatic to any diagnosis in our discipline, but this paradigm must shift to recognize that molecular diagnostics can provide closure where traditional tools have notable limitations.
Asunto(s)
Neoplasias Óseas , Fibroma Osificante , Fibroma , Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Anciano , Persona de Mediana Edad , Proteínas de Unión al ADN , Fibroma Osificante/diagnóstico , Fibroma Osificante/genética , Fibroma Osificante/patología , Osteogénesis , Proteínas del Grupo Polycomb , Recurrencia Local de Neoplasia , Fibroma/patología , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción con Cremalleras de Leucina de Carácter BásicoRESUMEN
Histone deacetylase inhibitors (iHDACs) have been extensively studied as enhancers of therapeutic protein production in recombinant Chinese hamster ovary (CHO) (rCHO) cell cultures. However, the addition of iHDACs reduces the viable cell concentration (VCC) in rCHO cell cultures, thereby reducing their potential to enhance therapeutic protein production. To mitigate the negative effects of iHDACs on VCC, screening using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based single-gene knockout (KO) library in rCHO cells was performed in the presence of CI994, a member of iHDACs, and 10 potential KO genes that enhanced the VCC of CI994-treated rCHO cells were identified. Among these, Bcor was validated as a promising KO target that improved VCC without negatively affecting the specific productivity in the presence of CI994. Bcor KO increased the VCC and therapeutic protein concentrations in both batch and fed-batch cultures in the presence of CI994. Taken together, these findings highlight the potential of the whole-genome CRISPR/Cas9-based single-gene KO cell library to identify KO target genes for the development of iHDAC-resistant rCHO cells for enhanced therapeutic protein production.
Asunto(s)
Sistemas CRISPR-Cas , Inhibidores de Histona Desacetilasas , Cricetinae , Animales , Cricetulus , Células CHO , Inhibidores de Histona Desacetilasas/farmacología , Proliferación CelularRESUMEN
INTRODUCTION: Undifferentiated small round-cell sarcomas with BCL6 corepressor (BCOR) alterations, such as an internal tandem duplication (ITD) within exon 15, are typically described as a pediatric group of Ewing-like small round-cell sarcomas. CASE PRESENTATION: In contrast to this notion, we report the case of a 71-year-old woman with a nasosinusal sarcoma featuring a BCOR ITD. To the best of our knowledge, this presence had not been previously documented in a sarcoma of the nasal and sinus cavities in an elderly patient. The identified duplication shares a similar minimal critical region as described in clear-cell sarcomas of the kidney in children. This alteration, located within the PCGF1 binding domain, is believed to disrupt the activity of PRC1.1. CONCLUSION: This case underscores the need for in-depth research into the molecular biology of these rare tumors and explores potential alternative treatment options. The patient achieved remission after two cycles of doxorubicin and cyclophosphamide chemotherapy, highlighting the promise of potential therapeutic options for BCOR ITD sarcomas.
RESUMEN
Sarcomas characterized by BCOR gene alterations, are a distinct clinico-pathological group of high-grade tumors, that represent 5% of small round cell tumors without EWSR or FUS fusion. Diverse genetic alterations characterize this group, including BCOR-CCNB3 gene fusion being the most common alteration and less frequently internal tandem duplications (ITDs). We present a compelling case of a 3-year-old girl diagnosed with a high-grade nasoethmoidal sarcoma exhibiting BCOR-ITD. The diagnostic process illustrates the histological and immunophenotypic spectrum, requiring an extensive immunohistochemical panel and diverse molecular tests for accurate classification. Additionally, this case highlights the challenges in detecting BCOR-ITDs using different NGS panels, advocating for alternative molecular approaches. Our patient after 10 months since diagnosis is alive with progressive disease. This emphasizes the urgency for ongoing research to refine diagnostic methods and develop effective therapeutic strategies for these rare and aggressive tumors.
RESUMEN
Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.
Asunto(s)
Defectos del Tabique Interventricular , Humanos , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Defectos del Tabique Interventricular/genética , Mutación , Factores de Transcripción/genéticaRESUMEN
Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan-Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings.
Asunto(s)
Biomarcadores de Tumor , Inmunohistoquímica , Proteínas Proto-Oncogénicas , Proteínas Represoras , Sarcoma Sinovial , Proteína con Dedos de Zinc GLI1 , Humanos , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patología , Sarcoma Sinovial/genética , Masculino , Femenino , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Adulto , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Anciano , Adulto Joven , Adolescente , Estimación de Kaplan-MeierRESUMEN
Synovial sarcomas are soft tissue tumours of uncertain origin, most commonly found in the upper or lower extremities. They are characterised by distinctive chromosomal rearrangements involving the gene SS18. Synovial sarcomas can occasionally arise also in visceral sites, but retroperitoneal SSs are very unusual. Among them, a few primary renal synovial sarcomas have been described in the scientific literature. Primary renal synovial sarcomas tend to be monophasic and often show cystic changes. Histologically, they can closely resemble other primary kidney tumours, mainly paediatric tumours such as nephroblastoma and clear cell sarcoma of the kidney. In the current work, a primary synovial sarcoma of the kidney with unusual morphological features (extensively myxoid stroma and immunohistochemical positivity for BCOR) is described. Molecular analysis, through targeted RNA sequencing, was of invaluable help in reaching the correct diagnosis. Despite locally advanced disease at presentation, the patient showed an unexpectedly brilliant response to chemotherapy.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Renales , Sarcoma Sinovial , Humanos , Sarcoma Sinovial/genética , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patología , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Masculino , Diagnóstico Diferencial , Diferenciación Celular , Femenino , Proteínas Proto-Oncogénicas , Proteínas RepresorasRESUMEN
BACKGROUND: Congenital heart disease (CHD) frequently manifests as a complex phenotype and approximately one-third of cases may be caused by genetic factors. BCOR, an X-linked gene encoding the corepressor of BCL6, has been demonstrated to be closely involved in human heart development. However, whether BCOR variants represent the genetic etiology underlying CHD needs further investigation. METHODS: We performed whole exome sequencing on CHD nuclear families and identified a candidate gene, BCOR, by robust bioinformatic analysis and medical literature searches. Targeted DNA sequencing of the candidate gene was conducted and then the association between variants and the risk of developing CHD was analyzed. The effects of BCOR mutations on gene expression, localization, protein interaction, and signaling pathways were evaluated in vitro. RESULTS: We identified a BCOR hemizygous missense variant (c.1448C>T, p.Pro483Leu) in a male proband presented with CHD/heterotaxy. Sanger sequencing confirmed that this variant was inherited from his asymptomatic mother. Interestingly, through literature searches, we observed another novel BCOR hemizygous missense variant (c.1619G>A, p.Arg540Gln) in a CHD patient with heterotaxy, supporting the pathogenic evidence of BCOR variants. Functional experiments conducted in vitro revealed that the variant p.Pro483Leu altered the subcellular localization of BCOR protein, disrupted its interaction with BCL6, and significantly promoted cell proliferation, whereas the variant p.Arg540Gln displayed no obvious effects. Nevertheless, transcriptional analysis revealed that down-regulation of BCOR substantially enhanced the activities of mitogen-activated protein and phosphoinositide 3-kinase-AKT signaling pathways, which are closely attributed to heart development. Targeted sequencing of 932 sporadic CHD patients enriched nine variants of BCOR predicted as likely rare and damaging and a septal defect was present in 81.8% (9/11) of them, including the two probands, which was consistent with the possible phenotype caused by BCOR defects. CONCLUSIONS: The findings of the present study indicate that variants in BCOR may predispose individuals to CHD in the Chinese Han population.
Asunto(s)
Cardiopatías Congénitas , Defectos de los Tabiques Cardíacos , Humanos , Masculino , Genes Ligados a X , Pueblos del Este de Asia , Fosfatidilinositol 3-Quinasas , Cardiopatías Congénitas/genética , Defectos de los Tabiques Cardíacos/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genéticaRESUMEN
In the pediatric population, BCL6-correpresor gene (BCOR)-upregulated tumors include primitive myxoid mesenchymal tumors/undifferentiated sarcomas (PMMTI/UND), clear cell sarcomas of the kidney (CCSK), and high-grade neuroepithelial tumors (HG-NET). We investigated DNA methylation (DNAm) and copy number variation (CNV) profiling in these tumors (N = 34) using an Illumina EPIC BeadChip to better define the potential use of these tools to confirm diagnosis and predict outcomes. Twenty-seven tumors from 25 patients (age range, 0-10 years), showed molecular confirmation of genetic abnormalities as follows: BCOR internal tandem duplication in 14 PMMTI/UND, 8 CCSK, and 3 HG-NET and YWHAE fusions in 2 PMMTI/UND. The remaining 7 cases lacking informative molecular data were analyzed by immunophenotyping and were included in the study as a training cohort, clearly separated from the main study group. These were 4 PMMTI, 1 HG-NET, and 1 CCSK in which poor RNA preservation precluded the confirmation of BCOR rearrangements and 1 CCSK in which no rearrangements were found. DNAm data were compared with those of brain tumor and/or sarcoma classifier. Differentially methylated regions (DMRs) were analyzed in the 3 groups. Twenty-two cases of the 24 molecularly confirmed PMMTI/UND and CCSK and 3 of 6 of those with only immunophenotyping were classified within the methylation class "BCOR-altered sarcoma family" with optimal calibrated scores. PMMTI/UND and CCSK showed similar methylation profiles, whereas thousands of DMRs and significantly enriched pathways were evident between soft tissue/kidney tumors and HG-NET. The CNV analysis showed an overall flat profile in 19 of the 31 evaluable tumors (8/10 CCSK; 9/18 PMMTI/UND; 2/4 HG-NET). The most frequent CNVs were 1q gain and 9p and 10q loss. Follow-up time data were available for 20 patients: ≥2 CNV significantly correlated with a worse overall survival rate. In conclusion, soft tissue and kidney BCOR sarcomas matched with BCOR-altered sarcoma methylation class, whereas those from the brain matched with the central nervous system tumor classifier HG-NET BCOR, supporting the notion that DNAm profiling is an informative diagnostic tool. CNV alterations were associated with a more aggressive clinical behavior.
Asunto(s)
Neoplasias Renales , Sarcoma , Neoplasias de los Tejidos Blandos , Niño , Humanos , Recién Nacido , Lactante , Preescolar , Metilación de ADN , Variaciones en el Número de Copia de ADN , Riñón , Neoplasias Renales/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genéticaRESUMEN
Sarcomas with BCOR genetic alterations (BCOR-associated sarcomas) represent a recently recognized family of soft tissue and bone tumors characterized by BCOR fusion, BCOR internal tandem duplication, or YWHAE::NUTM2B fusion. Histologically, the tumors demonstrate oval to spindle cell proliferation in a variably vascular stroma and overexpression of BCOR and SATB2. Herein, we describe 3 soft tissue sarcomas with KDM2B fusions that phenotypically and epigenetically match BCOR-associated sarcomas. The cases included 1 infant, 1 adolescent, and 1 older patient. All tumors showed histologic findings indistinguishable from those of BCOR-associated sarcomas and were originally diagnosed as such based on the phenotype. However, none of the tumors had BCOR or YWHAE genetic alterations. Instead, targeted RNA sequencing identified in-frame KDM2B::NUTM2B, KDM2B::CREBBP, and KDM2B::DUX4 fusions. KDM2B fusions were validated using reverse-transcription PCR, Sanger sequencing, and in situ hybridization assays. Genome-wide DNA methylation analysis matched all 3 tumors with BCOR-associated sarcomas using the Deutsches Krebsforschungszentrum (DKFZ) classifier and t-distributed stochastic neighbor embedding analysis. One localized tumor showed a flat genome-wide copy number profile, and the patient remained disease-free after treatment. The other tumors showed multiple copy number alterations, including MDM2/CDK4 amplification and/or CDKN2A/B loss, and both tumors metastasized, leading to the patient's death in one of the cases. When tested using KDM2B immunohistochemistry, all 3 KDM2B-rearranged sarcomas showed diffuse strong staining, and all 13 sarcomas with BCOR genetic alterations also demonstrated diffuse, strong, or weak staining. By contrast, among 72 mimicking tumors, only a subset of synovial sarcomas showed focal or diffuse weak KDM2B expression. In conclusion, our study suggests that KDM2B-rearranged soft tissue sarcomas belong to the BCOR-associated sarcoma family and expand its molecular spectrum. This may be related to the known molecular relationship between KDM2B and BCOR in the polycomb repressive complex 1.1. Immunohistochemical analysis of KDM2B is a potentially valuable diagnostic tool for BCOR-associated sarcomas, including those with KDM2B rearrangement.
Asunto(s)
Sarcoma Sinovial , Sarcoma , Neoplasias de los Tejidos Blandos , Lactante , Adolescente , Humanos , Proteínas Represoras/genética , Proteínas Represoras/análisis , Sarcoma/patología , Factores de Transcripción/genética , Reacción en Cadena de la Polimerasa , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Proteínas Proto-Oncogénicas/genéticaRESUMEN
PURPOSE: Review of the clinicopathologic and genetic features of early ependymal tumor with MN1-BEND2 fusion (EET MN1-BEND2), classical astroblastomas, and recently described related pediatric CNS tumors. I also briefly review general mechanisms of gene expression silencing by DNA methylation and chromatin remodeling, and genomic DNA methylation profiling as a powerful new tool for CNS tumor classification. METHODS: Literature review and illustration of tumor histopathologic features and prenatal gene expression timelines. RESULTS: Astroblastoma, originally descried by Bailey and Cushing in 1926, has been an enigmatic tumor. Whether they are of ependymal or astrocytic derivation was argued for decades. Recent genetic evidence supports existence of both ependymal and astrocytic astroblastoma-like tumors. Studies have shown that tumors exhibiting astroblastoma-like histology can be classified into discrete entities based on their genomic DNA methylation profiles, gene expression, and in some cases, the presence of unique gene fusions. One such tumor, EET MN1-BEND2 occurs mostly in female children, and has an overall very good prognosis with surgical management. It contains a gene fusion comprised of portions of the MN1 gene at chromosomal location 22q12.1 and the BEND2 gene at Xp22.13. Other emerging pediatric CNS tumor entities demonstrating ependymal or astroblastoma-like histological features also harbor gene fusions involving chromosome X, 11q22 and 22q12 breakpoint regions. CONCLUSIONS: Genomic DNA profiling has facilitated discovery of several new CNS tumor entities, however, traditional methods, such as immunohistochemistry, DNA or RNA sequencing, and cytogenetic studies, including fluorescence in situ hybridization, remain necessary for their accurate biological classification and diagnosis.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glioma , Neoplasias Neuroepiteliales , Neoplasias Supratentoriales , Niño , Femenino , Humanos , Neoplasias Encefálicas/patología , Hibridación Fluorescente in Situ , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/cirugía , Neoplasias Neuroepiteliales/metabolismo , Pronóstico , Transactivadores/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Pediatric renal tumors are a rare entity and majority of these tumors are accounted for by Wilms tumor. The second most common renal tumor is clear cell sarcoma of the kidney (CSSK). Most of the CSSK have either BCOR-internal tandem duplication (ITD) or YWHAE-NUTM2B/E fusion. The sarcomas with BCOR-CCNB3 fusion are well documented in soft tissue and bone tumors, but are extremely rare in the pediatric renal setting. We are reporting an extremely rare case of pediatric clear cell sarcoma of the kidney (CSSK) with BCOR-CCNB3 fusion, which was a diagnostic challenge on morphological grounds. A final diagnosis could only be reached after multiple reviews and NGS based RNA fusion testing. We have also performed a brief review of literature which revealed eight (8) other cases of this rare entity.
Asunto(s)
Neoplasias Renales , Sarcoma de Células Claras , Humanos , Niño , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/genética , Proteínas Represoras/genética , Factores de Transcripción , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/patología , Biomarcadores de Tumor/genética , Riñón/patología , Ciclina B , Proteínas Proto-Oncogénicas/genéticaRESUMEN
BACKGROUND: New entities in the classification of bone and soft tissue tumors have been identified by use of advanced molecular-genetic techniques, including next-generation sequencing. Clinicoradiologic and pathologic correlation supports diagnostic classification. METHODS: Tumors from four morphologically grouped areas are selected to enhance diagnosis and awareness among the multidisciplinary team. These include select round cell tumors, spindle cell tumors, targetable tyrosine kinase/RAS::MAPK pathway-ovoid (epithelioid to spindled) tumors, and giant-cell-rich tumors of bone and soft tissue. RESULTS: Round cell tumors of bone and soft tissue include prototypical Ewing sarcoma, newer sarcomas with BCOR genetic alteration and CIC-rearranged, as well as updates on FUS/EWSR1::NFATc2, an EWSR1 non-ETS tumor that is solid with additional amplified hybridization signal pattern of EWSR1. This FUS/EWSR1::NFATc2 fusion has now been observed in seemingly benign to low-grade intraosseous vascular-rich and simple (unicameral) bone cyst tumors. Select spindle cell tumors of bone and soft tissue include rhabdomyosarcoma with FUS/EWSR1::TFCP2, an intraosseous high-grade spindle cell tumor without matrix. Targetable tyrosine-kinase or RAS::MAPK pathway-tumors of bone and soft tissue include NTRK, ALK, BRAF, RAF1, RET, FGFR1, ABL1, EGFR, PDGFB, and MET with variable ovoid myopericytic to spindled pleomorphic features and reproducible clinicopathologic and radiologic clues to their diagnosis. Giant-cell-rich tumors of bone, joint, and soft tissue are now respectively characterized by H3F3A mutation, CSF1 rearrangement (targetable), and HMGA2::NCOR2 fusion. CONCLUSION: This article is an update for radiologists, oncologists, surgeons, and pathologists to recognize these novel ovoid, spindled, giant-cell-rich, and round cell tumors, for optimal diagnostic classification and multidisciplinary team patient care.
Asunto(s)
Rabdomiosarcoma , Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Sarcoma/patología , Sarcoma de Ewing/patología , Factores de Transcripción/genética , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/genética , Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genéticaRESUMEN
Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases.
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Neoplasias Renales , Sarcoma de Células Claras , Tumor de Wilms , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patología , Células HEK293 , Proteínas Represoras/genética , Neoplasias Renales/patología , Riñón/metabolismoRESUMEN
The year 2021 marked the centenary of the first publication of a cancer termed diffuse endothelioma of bone by James Ewing. Its unique features were apparent even in the first case series he described. This new diagnosis was clearly distinct from osteogenic sarcoma and myeloma, which were already well recognized at the time. We undertake this summary to better understanding Ewing sarcoma, contrasting the logarithmic evolution of the standard of care of systemic therapy for this and related diagnoses to the exponential understanding of the molecular biology of this family of tumors. We also outline in this manuscript how the finding of genomic relatives within Ewing sarcoma itself and related tumors, first noted nearly 40 years ago, helps us appreciate the need to find therapeutic plans that are specific for each small round blue cell tumor subtype. The advent of next generation sequencing regarding previously unknown small round blue cell tumor subtypes in many ways puts us back in the shoes of James Ewing in 1921, searching anew for clues leading to better treatments for increasingly rare cancer subsets.
Asunto(s)
Sarcoma de Ewing , Sarcoma , Biomarcadores de Tumor/genética , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma de Ewing/patología , Translocación GenéticaRESUMEN
BACKGROUND: The group of undifferentiated round cell sarcomas, according to the World Health Organization Classification, in addition to Ewing's sarcoma (ES), includes round cell sarcoma with rearrangement of the EWSR1 gene with partners not from the ETS gene family, sarcoma with BCOR gene alterations, CIC -rearranged sarcoma. Despite the fact that all tumors have clear histological and immunological criteria, their diagnosis can be difficult, given the fact that there are overlapping variants of the morphological picture and immunophenotype both within the group and with other round cell tumors. OBJECTIVE: Present a comparative analysis of genetically verified ES, sarcoma with BCOR gene alterations and CIC-rearranged sarcoma. MATERIAL AND METHODS: A comparative study of biopsy specimens of bones, soft tissues and internal organs was carried out in 118 patients with ES, 10 with BCOR gene alterations and 8 with CIC-rearranged sarcomas. All cases were genetically verified. The following research methods were used: histological, immunohistochemical, RT-PCR, RNA sequencing and FISH. RESULTS: Within our cohort, it was shown that ES predominantly affects bones, while soft tissue localization is more typical for the other two undifferentiated round cell sarcomas. Histologically, in the overwhelming majority of cases, ES is characterized by a monomorphic round-cell structure; on the contrary, heterogeneous structure is typical for sarcoma with alterations of the BCOR gene, CIC-rearranged sarcoma. High sensitivity and specificity of CD99/NKX2.2 co-expression for ES, BCOR/SATB2/TLE1 for sarcoma with BCOR gene alterations, high specificity and low sensitivity of WT1/ETV4 co-expression for CIC-rearranged sarcoma was shown. CONCLUSION: For the differential diagnosis of undifferentiated round-cell sarcomas, it is necessary to take into account the clinical, morphology when compared with the data of the IHC study, and verification by molecular genetic methods is necessary to improve the accuracy of diagnosis.
Asunto(s)
Sarcoma de Ewing , Sarcoma de Células Pequeñas , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Sarcoma/genética , Sarcoma de Células Pequeñas/diagnóstico , Sarcoma de Células Pequeñas/genética , Sarcoma de Células Pequeñas/patología , Factores de Transcripción , Neoplasias de los Tejidos Blandos/genética , Algoritmos , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genéticaRESUMEN
A full-term female infant was admitted at 5 hours after birth due to heart malformations found during the fetal period and cyanosis once after birth. Mmultiple malformations of eyes, face, limbs, and heart were noted. The whole-exome sequencing revealed a pathogenic heterozygous mutation, c.2428C>T(p.Arg810*), in the BCOR gene. The infant was then diagnosed with oculo-facio-cardio-dental syndrome. He received assisted ventilation to improve oxygenation and nutritional support during hospitalization. Right ventricular double outlet correction was performed 1 month after birth. Ocular lesions were followed up and scheduled for elective surgery. The possibility of oculo-facio-cardio-dental syndrome should be considered for neonates with multiple malformations of eyes, face, and heart, and genetic testing should be performed as early as possible to confirm the diagnosis; meanwhile, active ophthalmic and cardiovascular symptomatic treatment should be given to improve the prognosis.
Asunto(s)
Anomalías Múltiples , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Anomalías Múltiples/genética , Anomalías Múltiples/terapia , Catarata/genética , Cianosis , Proteínas Proto-Oncogénicas , Proteínas Represoras/genética , Cardiopatías Congénitas/genéticaRESUMEN
AIMS: JAZF1 translocation is the most common genetic change in low-grade (LG) endometrial stromal sarcoma (ESS), and YWHAE and BCOR translocations are common in high-grade (HG) ESS. Primary extrauterine ESS is rare, and there are limited data on molecular alterations in these tumours. METHODS AND RESULTS: Cases of primary extrauterine ESS, comprising eight LG-ESS cases and five HG-ESS cases were collected. Haematoxylin and eosin and immunohistochemical staining were used to observe the histomorphology and analyse related protein expression. JAZF1, YWHAE and BCOR rearrangements were explored with fluorescence in-situ hybridisation (FISH). In LG-ESS, the tumour cells resembled normal proliferative-phase endometrial stromal cells; CD10, oestrogen receptor and progesterone receptor were expressed in all eight cases. In HG-ESS, the tumour cells had uniform HG round and/or spindle morphology, sometimes with an LG component; CD10 was fully expressed in one case and focally expressed in four cases; BCOR was expressed in all five cases, and cyclin D1 in four of five cases. FISH analysis showed JAZF1 translocation in one of eight LG-ESS cases (12.5%). YWHAE translocation occurred in four of five HG-ESS cases, with a positivity rate of 80%. BCOR translocation was absent in all five cases. CONCLUSIONS: In extrauterine LG-ESS, the rate of JAZF1 rearrangement was significantly lower than in uterine LG-ESS. This result limited the value of JAZF1 translocation for diagnosis. YWHAE rearrangement is a common genetic change in extrauterine HG-ESS. Further studies are required to confirm these findings, especially in LG-ESS.