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1.
Nat Commun ; 12(1): 1407, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658498

RESUMO

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies.


Assuntos
Mutação , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Diferenciação Celular/genética , Metilação de DNA , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Crista Neural/patologia , Filogenia , Tumor Rabdoide/tratamento farmacológico , Proteína SMARCB1/genética , Análise de Célula Única , Serina-Treonina Quinases TOR/antagonistas & inibidores , Técnicas de Cultura de Tecidos/métodos
2.
Nature ; 592(7852): 80-85, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33692543

RESUMO

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation-within a few cell divisions of the zygote-of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.


Assuntos
Mosaicismo , Mutagênese , Mutação , Placenta/metabolismo , Biópsia , Massa Celular Interna do Blastocisto/citologia , Feminino , Genoma Humano/genética , Humanos , Mesoderma/citologia , Taxa de Mutação , Placenta/citologia , Gravidez , Trissomia/genética , Trofoblastos/citologia , Trofoblastos/metabolismo , Zigoto/citologia
3.
Sci Adv ; 7(6)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547074

RESUMO

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

5.
Cancer Discov ; 11(3): 542-544, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33589423

RESUMO

The key differences between tumors arising in children and those in adults stem from the cellular origin of cancer at different ages, with adult cancers arising within aging cell hierarchies, as a consequence of accumulated damage and mutagenesis, in contrast to childhood tumors that are born in aberrantly developing tissues. A distinct biological property of childhood tumor cells-a block of developmental maturation-may hold the key to advancing the treatment of childhood cancer beyond cytotoxic strategies.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33534137

RESUMO

In a case of astroblastoma, methylation analysis was uninformative, with no clustering with known CNS-HGNET-MN1 cases. Whole genome sequencing however identified a novel MN1-GTSE1 gene fusion (image), confirming the diagnosis of astroblastoma, as well as an EWSR1-PATZ1 gene fusion. Whole genome sequencing, alongside methylation profiling and conventional neuropathology, will continue to lead to improved diagnostics and prognostication for children with brain tumours.

7.
Science ; 371(6527)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479125

RESUMO

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.


Assuntos
Dermatite Atópica/embriologia , Dermatite Atópica/patologia , Psoríase/embriologia , Psoríase/patologia , Pele/embriologia , Animais , Atlas como Assunto , Movimento Celular , Conjuntos de Dados como Assunto , Células Dendríticas/imunologia , Dermatite Atópica/imunologia , Fármacos Dermatológicos/farmacologia , Humanos , Imunidade Inata/genética , Metotrexato/farmacologia , Camundongos , Fagócitos/imunologia , Psoríase/imunologia , Análise de Célula Única , Pele/citologia , Pele/imunologia , Linfócitos T/imunologia , Transcriptoma
8.
Lancet Child Adolesc Health ; 5(2): 142-154, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33484663

RESUMO

Childhood malignancies are rarely related to known environmental exposures, and it has become increasingly evident that inherited genetic factors play a substantial causal role. Large-scale sequencing studies have shown that approximately 10% of children with cancer have an underlying cancer predisposition syndrome. The number of recognised cancer predisposition syndromes and cancer predisposition genes are constantly growing. Imaging and laboratory technologies are improving, and knowledge of the range of tumours and risk of malignancy associated with cancer predisposition syndromes is increasing over time. Consequently, surveillance measures need to be constantly adjusted to address these new findings. Management recommendations for individuals with pathogenic germline variants in cancer predisposition genes need to be established through international collaborative studies, addressing issues such as genetic counselling, cancer prevention, cancer surveillance, cancer therapy, psychological support, and social-ethical issues. This Review represents the work by a group of experts from the European Society for Paediatric Oncology (SIOPE) and aims to summarise the current knowledge and define future research needs in this evolving field.


Assuntos
Predisposição Genética para Doença , Neoplasias/genética , Adolescente , Criança , Feminino , Testes Genéticos , Humanos , Masculino , Oncologia/métodos , Neoplasias/prevenção & controle , Medição de Risco
9.
10.
Gigascience ; 9(12)2020 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-33367645

RESUMO

BACKGROUND: Droplet-based single-cell RNA sequence analyses assume that all acquired RNAs are endogenous to cells. However, any cell-free RNAs contained within the input solution are also captured by these assays. This sequencing of cell-free RNA constitutes a background contamination that confounds the biological interpretation of single-cell transcriptomic data. RESULTS: We demonstrate that contamination from this "soup" of cell-free RNAs is ubiquitous, with experiment-specific variations in composition and magnitude. We present a method, SoupX, for quantifying the extent of the contamination and estimating "background-corrected" cell expression profiles that seamlessly integrate with existing downstream analysis tools. Applying this method to several datasets using multiple droplet sequencing technologies, we demonstrate that its application improves biological interpretation of otherwise misleading data, as well as improving quality control metrics. CONCLUSIONS: We present SoupX, a tool for removing ambient RNA contamination from droplet-based single-cell RNA sequencing experiments. This tool has broad applicability, and its application can improve the biological utility of existing and future datasets.

11.
N Engl J Med ; 383(19): 1860-1865, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33211929

RESUMO

Childhood tumors that occur synchronously in different anatomical sites usually represent metastatic disease. However, such tumors can be independent neoplasms. We investigated whether cases of bilateral neuroblastoma represented independent tumors in two children with pathogenic germline mutations by genotyping somatic mutations shared between tumors and blood. Our results suggested that in both children, the lineages that had given rise to the tumors had segregated within the first cell divisions of the zygote, without being preceded by a common premalignant clone. In one patient, the tumors had parallel evolution, including distinct second hits in SMARCA4, a putative predisposition gene for neuroblastoma. These findings portray cases of bilateral neuroblastoma as having independent lesions mediated by a germline predisposition. (Funded by Children with Cancer UK and Wellcome.).

13.
Nat Commun ; 11(1): 4767, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958743

RESUMO

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.


Assuntos
Artrite Psoriásica/imunologia , Linfócitos T CD8-Positivos/imunologia , Seleção Clonal Mediada por Antígeno , Receptores de Retorno de Linfócitos/metabolismo , Líquido Sinovial/imunologia , Artrite Psoriásica/sangue , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica , Humanos , Memória Imunológica , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Retorno de Linfócitos/genética , Análise de Célula Única , Membrana Sinovial/imunologia
14.
J Pathol ; 252(4): 433-440, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32866294

RESUMO

The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

16.
Science ; 367(6480)2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32079746

RESUMO

The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.


Assuntos
Atlas como Assunto , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Timo/crescimento & desenvolvimento , Timo/imunologia , Linfócitos T CD8-Positivos/citologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Humanos , RNA-Seq/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Célula Única/métodos , Timo/citologia
17.
Arch Dis Child Educ Pract Ed ; 105(2): 66-70, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31278078

RESUMO

Leukaemia is the most common cancer of childhood. Most children with a new diagnosis of leukaemia are clinically stable at initial presentation. However, there are a number of life-threatening complications that have to be considered and monitored for. These complications include sepsis, tumour lysis syndrome, mediastinal masses, bleeding and pain. The aim of this article is to equip the general paediatrician with a framework for managing children with suspected leukaemia, prior to transfer to the primary treatment centre. The presentation, diagnosis and definitive treatment of acute leukaemia is not in the remit of this article.

18.
Science ; 366(6470): 1247-1251, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806814

RESUMO

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.


Assuntos
Células Clonais , Metilação de DNA , Neoplasias Renais/genética , Rim/patologia , Lesões Pré-Cancerosas/patologia , Tumor de Wilms/genética , Criança , Humanos , Rim/embriologia , Neoplasias Renais/patologia , Mutação , Filogenia , Tumor de Wilms/patologia
19.
Science ; 365(6460): 1461-1466, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31604275

RESUMO

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.


Assuntos
Rim/imunologia , Macrófagos/citologia , Neutrófilos/citologia , Adulto , Animais , Células Epiteliais/citologia , Feminino , Feto , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Rim/anatomia & histologia , Rim/citologia , Linfócitos/citologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/citologia , RNA-Seq , Análise de Célula Única , Infecções Urinárias/imunologia
20.
Arch Dis Child Educ Pract Ed ; 104(6): 298-303, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31048342

RESUMO

OBJECTIVES: To present a structured approach to the management of a child with a mediastinal mass presenting to the emergency department. To raise awareness of presenting features of less-obvious mediastinal masses and to encourage consideration of mediastinal masses in differential diagnoses. METHODS: Review of the relevant literature and review of London Paediatric Cancer Network supportive guidelines and subsequent description of the approach to a child presenting with features suggestive of a mediastinal mass. CONCLUSIONS: A systematic approach to history taking, clinical examination and investigation of a child presenting with a mediastinal mass will assist in the safe and timely management of children presenting when they are critically unwell. Anticipation of potential management complications and early transfer for ongoing management will improve patient outcomes and minimise morbidity.


Assuntos
Neoplasias do Mediastino/diagnóstico , Manuseio das Vias Aéreas , Diagnóstico Diferencial , Humanos , Mediastino/diagnóstico por imagem , Anamnese , Exame Físico
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