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1.
Cell ; 2023 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-37385248

RESUMEN

Certain cancer types afflict female and male patients disproportionately. The reasons include differences in male/female physiology, effect of sex hormones, risk behavior, environmental exposures, and genetics of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in >5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age and survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited.

2.
Cell ; 184(17): 4512-4530.e22, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34343496

RESUMEN

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.


Asunto(s)
Receptores CXCR6/metabolismo , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral , Animales , Antígeno B7-H1/metabolismo , Comunicación Celular , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Quimiocina CXCL16 , Células Dendríticas/metabolismo , Interleucina-12/metabolismo , Interleucina-15/metabolismo , Ligandos , Ganglios Linfáticos/metabolismo , Melanoma/inmunología , Melanoma/patología , Ratones Endogámicos C57BL
3.
Cell ; 178(4): 835-849.e21, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31327527

RESUMEN

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.


Asunto(s)
Neoplasias Encefálicas/genética , Plasticidad de la Célula/genética , Glioblastoma/genética , Adolescente , Anciano , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Linaje de la Célula/genética , Niño , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Heterogeneidad Genética , Glioblastoma/patología , Xenoinjertos , Humanos , Lactante , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Persona de Mediana Edad , Mutación , RNA-Seq , Análisis de la Célula Individual/métodos , Microambiente Tumoral/genética
4.
Cell ; 164(3): 538-49, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26806129

RESUMEN

Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.


Asunto(s)
Daño del ADN , Análisis Mutacional de ADN , Reparación del ADN , Neoplasias/genética , Replicación del ADN , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Mutación , Neoplasias/patología , Transcripción Genética
5.
Cell ; 157(3): 580-94, 2014 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-24726434

RESUMEN

Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP:


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioblastoma/genética , Glioblastoma/patología , Células Madre Neoplásicas/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias Encefálicas/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Células Cultivadas , Proteínas Co-Represoras/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Humanos , Células Madre Neoplásicas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos , Elementos Reguladores de la Transcripción , Factores de Transcripción/metabolismo
6.
Nature ; 594(7862): 283-288, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33981036

RESUMEN

Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle1-3. Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci4-10, but how transcription promotes HR is poorly understood. Here we develop an assay to assess the effect of local transcription on HR. Using this assay, we find that transcription stimulates HR to a substantial extent. Tethering RNA transcripts to the vicinity of DSBs recapitulates the effects of local transcription, which suggests that transcription enhances HR through RNA transcripts. Tethered RNA transcripts stimulate HR in a sequence- and orientation-dependent manner, indicating that they function by forming DNA-RNA hybrids. In contrast to most HR proteins, RAD51-associated protein 1 (RAD51AP1) only promotes HR when local transcription is active. RAD51AP1 drives the formation of R-loops in vitro and is required for tethered RNAs to stimulate HR in cells. Notably, RAD51AP1 is necessary for the DSB-induced formation of DNA-RNA hybrids in donor DNA, linking R-loops to D-loops. In vitro, RAD51AP1-generated R-loops enhance the RAD51-mediated formation of D-loops locally and give rise to intermediates that we term 'DR-loops', which contain both DNA-DNA and DNA-RNA hybrids and favour RAD51 function. Thus, at DSBs in transcribed regions, RAD51AP1 promotes the invasion of RNA transcripts into donor DNA, and stimulates HR through the formation of DR-loops.


Asunto(s)
ADN/genética , ADN/metabolismo , Recombinación Homóloga/genética , Estructuras R-Loop/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Línea Celular , ADN/química , Roturas del ADN de Doble Cadena , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Genes/genética , Genes Reporteros/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Técnicas In Vitro , ARN Mensajero/química , Proteínas de Unión al ARN/metabolismo , Recombinasa Rad51/metabolismo
7.
Nature ; 578(7793): 102-111, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32025015

RESUMEN

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.


Asunto(s)
Genoma Humano/genética , Mutación/genética , Neoplasias/genética , Roturas del ADN , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Mutación INDEL
9.
Acta Haematol ; 146(4): 316-321, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37285821

RESUMEN

The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.


Asunto(s)
Trastornos Mieloproliferativos , Neoplasias , Humanos , Mesilato de Imatinib/uso terapéutico , Diagnóstico Tardío , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Hibridación Fluorescente in Situ , Benzamidas , Proteínas de Fusión Oncogénica/genética , Trastornos Mieloproliferativos/tratamiento farmacológico , Neoplasias/tratamiento farmacológico
10.
Nature ; 547(7661): 55-60, 2017 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-28658208

RESUMEN

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.


Asunto(s)
Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica/genética , Mutación , Regiones Promotoras Genéticas/genética , Estudios de Cohortes , Factores de Transcripción E2F/metabolismo , Exoma/genética , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Unión Proteica/genética , ARN Largo no Codificante/genética , Receptores de Estrógenos/antagonistas & inhibidores
11.
BMC Bioinformatics ; 22(1): 611, 2021 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-34952565

RESUMEN

BACKGROUND: Exogenous cDNA introduced into an experimental system, either intentionally or accidentally, can appear as added read coverage over that gene in next-generation sequencing libraries derived from this system. If not properly recognized and managed, this cross-contamination with exogenous signal can lead to incorrect interpretation of research results. Yet, this problem is not routinely addressed in current sequence processing pipelines. RESULTS: We present cDNA-detector, a computational tool to identify and remove exogenous cDNA contamination in DNA sequencing experiments. We demonstrate that cDNA-detector can identify cDNAs quickly and accurately from alignment files. A source inference step attempts to separate endogenous cDNAs (retrocopied genes) from potential cloned, exogenous cDNAs. cDNA-detector provides a mechanism to decontaminate the alignment from detected cDNAs. Simulation studies show that cDNA-detector is highly sensitive and specific, outperforming existing tools. We apply cDNA-detector to several highly-cited public databases (TCGA, ENCODE, NCBI SRA) and show that contaminant genes appear in sequencing experiments where they lead to incorrect coverage peak calls. CONCLUSIONS: cDNA-detector is a user-friendly and accurate tool to detect and remove cDNA detection in NGS libraries. This two-step design reduces the risk of true variant removal since it allows for manual review of candidates. We find that contamination with intentionally and accidentally introduced cDNAs is an underappreciated problem even in widely-used consortium datasets, where it can lead to spurious results. Our findings highlight the importance of sensitive detection and removal of contaminant cDNA from NGS libraries before downstream analysis.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Simulación por Computador , ADN Complementario/genética , Biblioteca de Genes , Análisis de Secuencia de ADN
12.
Nat Methods ; 15(7): 531-534, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29941871

RESUMEN

Comparison of sequencing data from a tumor sample with data from a matched germline control is a key step for accurate detection of somatic mutations. Detection sensitivity for somatic variants is greatly reduced when the matched normal sample is contaminated with tumor cells. To overcome this limitation, we developed deTiN, a method that estimates the tumor-in-normal (TiN) contamination level and, in cases affected by contamination, improves sensitivity by reclassifying initially discarded variants as somatic.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Análisis de Secuencia de ADN/métodos , Simulación por Computador , Humanos , Mutación
13.
Genes Dev ; 26(17): 1926-44, 2012 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-22899010

RESUMEN

Growth of numerous cancer types is believed to be driven by a subpopulation of poorly differentiated cells, often referred to as cancer stem cells (CSCs), that have the capacity for self-renewal, tumor initiation, and generation of nontumorigenic progeny. Despite their potentially key role in tumor establishment and maintenance, the energy requirements of these cells and the mechanisms that regulate their energy production are unknown. Here, we show that the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2, IGF2BP2) regulates oxidative phosphorylation (OXPHOS) in primary glioblastoma (GBM) sphere cultures (gliomaspheres), an established in vitro model for CSC expansion. We demonstrate that IMP2 binds several mRNAs that encode mitochondrial respiratory chain complex subunits and that it interacts with complex I (NADH:ubiquinone oxidoreductase) proteins. Depletion of IMP2 in gliomaspheres decreases their oxygen consumption rate and both complex I and complex IV activity that results in impaired clonogenicity in vitro and tumorigenicity in vivo. Importantly, inhibition of OXPHOS but not of glycolysis abolishes GBM cell clonogenicity. Our observations suggest that gliomaspheres depend on OXPHOS for their energy production and survival and that IMP2 expression provides a key mechanism to ensure OXPHOS maintenance by delivering respiratory chain subunit-encoding mRNAs to mitochondria and contributing to complex I and complex IV assembly.


Asunto(s)
Glioblastoma/metabolismo , Células Madre Neoplásicas/metabolismo , Fosforilación Oxidativa , Proteínas de Unión al ARN/metabolismo , Animales , Encéfalo/metabolismo , Hipoxia de la Célula/fisiología , Línea Celular , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Unión Proteica , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/genética , Rotenona/farmacología , Células Tumorales Cultivadas , Desacopladores/farmacología
14.
N Engl J Med ; 372(26): 2481-98, 2015 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-26061751

RESUMEN

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).


Asunto(s)
ADN de Neoplasias/análisis , Genes p53 , Glioma/genética , Mutación , Adolescente , Adulto , Anciano , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Análisis por Conglomerados , Femenino , Glioblastoma/genética , Glioma/metabolismo , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Modelos de Riesgos Proporcionales , Análisis de Secuencia de ADN , Transducción de Señal
15.
Proc Natl Acad Sci U S A ; 111(51): E5564-73, 2014 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-25512523

RESUMEN

Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.


Asunto(s)
Neoplasias Óseas/metabolismo , Genoma Humano , Osteosarcoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Línea Celular Tumoral , Proliferación Celular , Heterogeneidad Genética , Mutación de Línea Germinal , Humanos , Osteosarcoma/genética , Osteosarcoma/patología , Proteína p53 Supresora de Tumor/genética
16.
Nature ; 459(7247): 657-62, 2009 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-19465905

RESUMEN

Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.


Asunto(s)
Candida/fisiología , Candida/patogenicidad , Evolución Molecular , Genoma Fúngico/genética , Reproducción/genética , Candida/clasificación , Candida/genética , Codón/genética , Secuencia Conservada , Diploidia , Genes Fúngicos/genética , Meiosis/genética , Polimorfismo Genético , Saccharomyces/clasificación , Saccharomyces/genética , Virulencia/genética
17.
Nat Cell Biol ; 26(6): 975-990, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38862786

RESUMEN

Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.


Asunto(s)
Glutatión Transferasa , Neoplasias Pancreáticas , Microambiente Tumoral , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/metabolismo , Animales , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Fibronectinas/metabolismo , Metástasis de la Neoplasia , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/enzimología , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Ratones , Femenino , Ratones Endogámicos C57BL
18.
PLoS Genet ; 4(10): e1000242, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18974828

RESUMEN

In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes -- the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.


Asunto(s)
Cromatina/metabolismo , Islas de CpG , Células Madre Embrionarias/metabolismo , Epigénesis Genética , Genoma Humano , Genoma , Proteínas Represoras/metabolismo , Animales , Cromatina/química , Inmunoprecipitación de Cromatina , Mapeo Cromosómico , Biología Computacional , Histonas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji , Metilación , Ratones , Oxidorreductasas N-Desmetilantes/metabolismo , Células Madre Pluripotentes/metabolismo , Proteínas del Grupo Polycomb , Regiones Promotoras Genéticas , Estructura Terciaria de Proteína , Proteínas Represoras/genética
19.
Cell Rep ; 34(5): 108707, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33535033

RESUMEN

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/genética , Taquicininas/metabolismo , Secuenciación Completa del Genoma/métodos , Humanos
20.
Nat Commun ; 11(1): 5040, 2020 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-33028839

RESUMEN

Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2 .


Asunto(s)
Genoma Humano/genética , Genómica/normas , Neoplasias/genética , Control de Calidad , Mapeo Cromosómico/normas , Cromosomas Humanos/genética , Análisis Mutacional de ADN/normas , Femenino , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Masculino , Mutación , Programas Informáticos , Secuenciación Completa del Genoma/normas
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