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1.
Cell ; 173(4): 1003-1013.e15, 2018 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-29681457

RESUMEN

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.


Asunto(s)
Neoplasias de la Próstata/patología , Biomarcadores de Tumor/sangre , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Clasificación del Tumor , Recurrencia Local de Neoplasia , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Neoplasias de la Próstata/clasificación , Neoplasias de la Próstata/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
2.
Nature ; 541(7637): 359-364, 2017 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-28068672

RESUMEN

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.


Asunto(s)
Genoma Humano/genética , Genómica , Mutación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Cromotripsis , Variaciones en el Número de Copia de ADN , Metilación de ADN , Exoma/genética , Humanos , Masculino , Metástasis de la Neoplasia/genética , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Recurrencia
3.
Nat Biotechnol ; 38(1): 97-107, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31919445

RESUMEN

Tumor DNA sequencing data can be interpreted by computational methods that analyze genomic heterogeneity to infer evolutionary dynamics. A growing number of studies have used these approaches to link cancer evolution with clinical progression and response to therapy. Although the inference of tumor phylogenies is rapidly becoming standard practice in cancer genome analyses, standards for evaluating them are lacking. To address this need, we systematically assess methods for reconstructing tumor subclonality. First, we elucidate the main algorithmic problems in subclonal reconstruction and develop quantitative metrics for evaluating them. Then we simulate realistic tumor genomes that harbor all known clonal and subclonal mutation types and processes. Finally, we benchmark 580 tumor reconstructions, varying tumor read depth, tumor type and somatic variant detection. Our analysis provides a baseline for the establishment of gold-standard methods to analyze tumor heterogeneity.


Asunto(s)
Algoritmos , Neoplasias/patología , Células Clonales , Simulación por Computador , Variaciones en el Número de Copia de ADN/genética , Dosificación de Gen , Genoma , Humanos , Mutación/genética , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Estándares de Referencia
4.
Nat Med ; 25(10): 1615-1626, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31591588

RESUMEN

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.


Asunto(s)
Metilación de ADN/genética , Epigenoma/genética , Mutación de Línea Germinal/genética , Neoplasias de la Próstata/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Genoma Humano/genética , Humanos , Masculino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/genética , Sitios de Carácter Cuantitativo/genética
5.
Genome Biol ; 19(1): 188, 2018 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-30400818

RESUMEN

BACKGROUND: The phenotypes of cancer cells are driven in part by somatic structural variants. Structural variants can initiate tumors, enhance their aggressiveness, and provide unique therapeutic opportunities. Whole-genome sequencing of tumors can allow exhaustive identification of the specific structural variants present in an individual cancer, facilitating both clinical diagnostics and the discovery of novel mutagenic mechanisms. A plethora of somatic structural variant detection algorithms have been created to enable these discoveries; however, there are no systematic benchmarks of them. Rigorous performance evaluation of somatic structural variant detection methods has been challenged by the lack of gold standards, extensive resource requirements, and difficulties arising from the need to share personal genomic information. RESULTS: To facilitate structural variant detection algorithm evaluations, we create a robust simulation framework for somatic structural variants by extending the BAMSurgeon algorithm. We then organize and enable a crowdsourced benchmarking within the ICGC-TCGA DREAM Somatic Mutation Calling Challenge (SMC-DNA). We report here the results of structural variant benchmarking on three different tumors, comprising 204 submissions from 15 teams. In addition to ranking methods, we identify characteristic error profiles of individual algorithms and general trends across them. Surprisingly, we find that ensembles of analysis pipelines do not always outperform the best individual method, indicating a need for new ways to aggregate somatic structural variant detection approaches. CONCLUSIONS: The synthetic tumors and somatic structural variant detection leaderboards remain available as a community benchmarking resource, and BAMSurgeon is available at https://github.com/adamewing/bamsurgeon .


Asunto(s)
Benchmarking , Simulación por Computador , Colaboración de las Masas , Variación Genética , Genoma Humano , Genómica/métodos , Neoplasias/genética , Algoritmos , Bases de Datos Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Programas Informáticos
6.
Nat Commun ; 8: 13671, 2017 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-28067867

RESUMEN

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.


Asunto(s)
Proteína BRCA2/genética , Carcinoma Ductal/genética , Regulación Neoplásica de la Expresión Génica , Mutación de Línea Germinal , Complejo Mediador/genética , Neoplasias de la Próstata/genética , Anciano , Proteína BRCA2/deficiencia , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patología , Carcinoma Ductal/cirugía , Análisis Mutacional de ADN , Epigénesis Genética , Evolución Molecular , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Inestabilidad Genómica , Heterocigoto , Humanos , Masculino , Complejo Mediador/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica , Próstata/metabolismo , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estudios Retrospectivos , Secuenciación Completa del Genoma
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