RESUMEN
Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.
Asunto(s)
Desaminasas APOBEC/genética , Neoplasias/genética , Desaminasas APOBEC/metabolismo , Línea Celular , Línea Celular Tumoral , ADN/metabolismo , Análisis Mutacional de ADN/métodos , Bases de Datos Genéticas , Exoma , Genoma Humano/genética , Xenoinjertos , Humanos , Mutagénesis , Mutación/genética , Tasa de Mutación , Retroelementos , Secuenciación del Exoma/métodosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample.â'. The Article has not been corrected.
RESUMEN
Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
Asunto(s)
Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/genética , Mutación , Adulto , Células Sanguíneas/metabolismo , Linaje de la Célula/genética , Genoma Humano/genética , Mutación de Línea Germinal/genética , Humanos , Mosaicismo , Mutagénesis , Tasa de MutaciónAsunto(s)
Aclimatación , Atletas , Calor Extremo/efectos adversos , Golpe de Calor/etiología , Golpe de Calor/prevención & control , Acondicionamiento Físico Humano , Seguridad , Femenino , Frecuencia Cardíaca , Golpe de Calor/fisiopatología , Humanos , Masculino , Medicina Deportiva , Baño de Vapor , Sudoración , TelemetríaAsunto(s)
Biodiversidad , Conservación de los Recursos Naturales/legislación & jurisprudencia , Política Ambiental/legislación & jurisprudencia , Remodelación Urbana , Animales , Animales Salvajes/virología , COVID-19/prevención & control , COVID-19/transmisión , China , Ciudades/economía , Ciudades/estadística & datos numéricos , Abastecimiento de Alimentos/legislación & jurisprudencia , Encuestas y Cuestionarios , Remodelación Urbana/economía , Zoonosis Virales/epidemiología , Zoonosis Virales/prevención & controlRESUMEN
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Genoma Humano/genética , Mutación/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Replicación del ADN/genética , ADN de Neoplasias/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Genómica , Humanos , Masculino , Mutagénesis , Tasa de Mutación , Oncogenes/genética , Reparación del ADN por Recombinación/genéticaRESUMEN
BACKGROUND: Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. METHODS: We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort. RESULTS: A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy. CONCLUSIONS: Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms. Integration of genomic data with clinical variables enabled the personalized predictions of patients' outcomes and may support the treatment of patients with myeloproliferative neoplasms. (Funded by the Wellcome Trust and others.).