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1.
Cell ; 184(8): 2239-2254.e39, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33831375

RESUMEN

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.


Asunto(s)
Heterogeneidad Genética , Neoplasias/genética , Variaciones en el Número de Copia de ADN , ADN de Neoplasias/química , ADN de Neoplasias/metabolismo , Bases de Datos Genéticas , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma
2.
Cell ; 155(3): 567-81, 2013 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-24139898

RESUMEN

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.


Asunto(s)
Cromosomas Humanos X , Mutación , Neoplasias/genética , Inactivación del Cromosoma X , Adulto , Anciano , Replicación del ADN , Femenino , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Polimorfismo de Nucleótido Simple , Fase S
3.
Nature ; 606(7916): 976-983, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35705807

RESUMEN

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA1. The broad genomic complexity caused by CIN is a hallmark of cancer2; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.


Asunto(s)
Inestabilidad Cromosómica , Neoplasias , Inestabilidad Cromosómica/genética , Recombinación Homóloga/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
4.
Nature ; 583(7815): 265-270, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32581361

RESUMEN

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.


Asunto(s)
Segregación Cromosómica/genética , Evolución Molecular , Genoma/genética , Neoplasias/genética , Alelos , Animales , Reparación del ADN , Replicación del ADN , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Mutación , Neoplasias/patología , Selección Genética , Transducción de Señal , Intercambio de Cromátides Hermanas , Transcripción Genética , Quinasas raf/metabolismo , Proteínas ras/metabolismo
5.
Nat Genet ; 52(6): 582-593, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32483290

RESUMEN

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.


Asunto(s)
Cistadenocarcinoma Seroso/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/tratamiento farmacológico , Microambiente Tumoral/inmunología , Animales , Cisplatino/inmunología , Cisplatino/farmacología , Estudios de Cohortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/inmunología , Variaciones en el Número de Copia de ADN , Femenino , Perfilación de la Expresión Génica/estadística & datos numéricos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes myc , Humanos , Células Asesinas Naturales/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Ratones , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Análisis de Componente Principal , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Vía de Señalización Wnt
6.
Nat Commun ; 6: 10001, 2015 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-26647970

RESUMEN

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia Linfoide/genética , Meduloblastoma/genética , Mutación , Genoma Humano , Humanos
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