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1.
Cell ; 179(5): 1207-1221.e22, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730858

RESUMO

Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.


Assuntos
Replicação do DNA/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Célula Única , Aneuploidia , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Forma Celular , Sobrevivência Celular , Cromossomos Humanos/genética , Células Clonais , Elementos de DNA Transponíveis/genética , Diploide , Feminino , Genótipo , Humanos , Masculino , Camundongos , Mutação/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética
2.
Cell ; 173(7): 1755-1769.e22, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29754820

RESUMO

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Antígenos CD8/metabolismo , Análise por Conglomerados , Feminino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Perda de Heterozigosidade , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Sequenciamento Completo do Genoma , Adulto Jovem
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