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1.
Nature ; 587(7832): 126-132, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32879494

RESUMEN

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.


Asunto(s)
Inestabilidad Cromosómica/genética , Evolución Molecular , Cariotipo , Metástasis de la Neoplasia/genética , Neoplasias/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 8/genética , Células Clonales/metabolismo , Células Clonales/patología , Ciclina E/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Mutagénesis , Metástasis de la Neoplasia/patología , Neoplasias/patología , Proteínas Oncogénicas/genética
2.
Blood ; 136(7): 885-897, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32294156

RESUMEN

Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy.


Asunto(s)
Anemia Aplásica/inmunología , Apoptosis/efectos de los fármacos , Proteína Ligando Fas/farmacología , Interleucina-2/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Anemia Aplásica/patología , Animales , Apoptosis/inmunología , Células Cultivadas , Femenino , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/patología , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Interleucina-2/deficiencia , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Linfocitos T Reguladores/fisiología
3.
Nucleic Acids Res ; 44(D1): D992-9, 2016 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-26516186

RESUMEN

The Network of Cancer Genes (NCG, http://ncg.kcl.ac.uk/) is a manually curated repository of cancer genes derived from the scientific literature. Due to the increasing amount of cancer genomic data, we have introduced a more robust procedure to extract cancer genes from published cancer mutational screenings and two curators independently reviewed each publication. NCG release 5.0 (August 2015) collects 1571 cancer genes from 175 published studies that describe 188 mutational screenings of 13 315 cancer samples from 49 cancer types and 24 primary sites. In addition to collecting cancer genes, NCG also provides information on the experimental validation that supports the role of these genes in cancer and annotates their properties (duplicability, evolutionary origin, expression profile, function and interactions with proteins and miRNAs).


Asunto(s)
Bases de Datos Genéticas , Genes Relacionados con las Neoplasias , Mutación , Curaduría de Datos , Humanos , Anotación de Secuencia Molecular , Neoplasias/genética
4.
Nat Cancer ; 5(7): 1102-1120, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38565920

RESUMEN

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.


Asunto(s)
Vía de Señalización Hippo , Proteínas Serina-Treonina Quinasas , Factores de Transcripción , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Factores de Transcripción/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratones , Línea Celular Tumoral , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas de Unión al ADN/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción de Dominio TEA , Proteínas ras/metabolismo , Femenino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
5.
Nat Commun ; 14(1): 3907, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37400441

RESUMEN

YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Neoplasias , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Señalizadoras YAP , Epigenómica , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transducción de Señal/genética
6.
Elife ; 102021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33929322

RESUMEN

High-dimensional cytometry is an innovative tool for immune monitoring in health and disease, and it has provided novel insight into the underlying biology as well as biomarkers for a variety of diseases. However, the analysis of large multiparametric datasets usually requires specialist computational knowledge. Here, we describe ImmunoCluster (https://github.com/kordastilab/ImmunoCluster), an R package for immune profiling cellular heterogeneity in high-dimensional liquid and imaging mass cytometry, and flow cytometry data, designed to facilitate computational analysis by a nonspecialist. The analysis framework implemented within ImmunoCluster is readily scalable to millions of cells and provides a variety of visualization and analytical approaches, as well as a rich array of plotting tools that can be tailored to users' needs. The protocol consists of three core computational stages: (1) data import and quality control; (2) dimensionality reduction and unsupervised clustering; and (3) annotation and differential testing, all contained within an R-based open-source framework.


Asunto(s)
Alergia e Inmunología , Biología Computacional/métodos , Citometría de Flujo/métodos , Algoritmos , Linfocitos B/citología , Linfocitos B/inmunología , Análisis de Datos , Humanos
7.
Nat Genet ; 52(3): 283-293, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32139907

RESUMEN

Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Duplicación de Gen , Genoma Humano/genética , Neoplasias Pulmonares/genética , Proteínas Supresoras de Tumor/genética , Estudios de Cohortes , Simulación por Computador , Variaciones en el Número de Copia de ADN , Evolución Molecular , Humanos , Estudios Longitudinales , Pérdida de Heterocigocidad , Mutación , Estudios Prospectivos
8.
Nat Commun ; 10(1): 3101, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31308377

RESUMEN

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.


Asunto(s)
Adenocarcinoma/genética , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/genética , Perfilación de la Expresión Génica/métodos , Medicina de Precisión/métodos , Antineoplásicos/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Biología Computacional/métodos , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inestabilidad Genómica , Humanos , Aprendizaje Automático , Modelos Genéticos , Familia de Multigenes/efectos de los fármacos , Tasa de Mutación , Polimorfismo de Nucleótido Simple
9.
Cell Rep ; 26(3): 555-563.e6, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30650350

RESUMEN

We provide a catalog for the effects of the human kinome on cell survival in response to DNA-damaging agents, covering all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA-damaging agents, including seven commonly used chemotherapeutics, we identified examples of vulnerability and resistance that are kinase specific. To investigate synthetic lethal interactions, we tested the response to carmustine for 25 cell lines by establishing a phenotypic fluorescence-activated cell sorting (FACS) assay designed to validate gene-drug interactions. We show apoptosis, cell cycle changes, and DNA damage and proliferation after alkylation- or crosslink-induced damage. In addition, we reconstitute the cellular sensitivity of DYRK4, EPHB6, MARK3, and PNCK as a proof of principle for our study. Furthermore, using global phosphoproteomics on cells lacking MARK3, we provide evidence for its role in the DNA damage response. Our data suggest that cancers with inactivating mutations in kinases, including MARK3, are particularly vulnerable to alkylating chemotherapeutic agents.


Asunto(s)
Daño del ADN/fisiología , Humanos , Transducción de Señal
11.
Trends Cancer ; 2(4): 160-162, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-28741568

RESUMEN

Cancer genomes acquire somatic alterations that largely differ between and within cancer types. Several of these alterations inactivate genes that are normally functional with no deleterious consequences on cancer cells due to genetic redundancy. Here we discuss how this leads to cancer synthetic dependencies that can be exploited in therapy.


Asunto(s)
Neoplasias/genética , Animales , Predisposición Genética a la Enfermedad , Genoma , Humanos , Mutación
12.
Nat Commun ; 7: 12072, 2016 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-27377421

RESUMEN

Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation.


Asunto(s)
Neoplasias Colorrectales/genética , Heterogeneidad Genética , Mutación de Línea Germinal , Proteínas de Neoplasias/genética , Neoplasias Primarias Múltiples/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Células Clonales , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Citocinas/genética , Citocinas/inmunología , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Proteínas de Neoplasias/inmunología , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología
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