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1.
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
2.
Bioinformatics ; 34(6): 1034-1036, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29112706

RESUMEN

Summary: The NanoString System is a well-established technology for measuring RNA and DNA abundance. Although it can estimate copy number variation, relatively few tools support analysis of these data. To address this gap, we created NanoStringNormCNV, an R package for pre-processing and copy number variant calling from NanoString data. This package implements algorithms for pre-processing, quality-control, normalization and copy number variation detection. A series of reporting and data visualization methods support exploratory analyses. To demonstrate its utility, we apply it to a new dataset of 96 genes profiled on 41 prostate tumour and 24 matched normal samples. Availability and implementation: NanoStringNormCNV is implemented in R and is freely available at http://labs.oicr.on.ca/boutros-lab/software/nanostringnormcnv. Contact: paul.boutros@oicr.on.ca. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Variaciones en el Número de Copia de ADN , Análisis de Secuencia de ADN/métodos , Programas Informáticos , Algoritmos , Genómica/métodos , Humanos , Masculino , Neoplasias de la Próstata/genética , Control de Calidad
3.
Nat Methods ; 12(7): 623-30, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25984700

RESUMEN

The detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.


Asunto(s)
Benchmarking , Colaboración de las Masas , Genoma , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Algoritmos , Humanos
4.
Nat Genet ; 51(2): 308-318, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30643250

RESUMEN

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.


Asunto(s)
Hipoxia/genética , Neoplasias de la Próstata/genética , Hipoxia Tumoral/genética , Alelos , Línea Celular Tumoral , Cromotripsis , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Inestabilidad Genómica/genética , Humanos , Masculino , MicroARNs/genética , Células PC-3 , Fosfohidrolasa PTEN/genética , Telómero/genética
5.
Oncotarget ; 9(32): 22460-22479, 2018 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-29854292

RESUMEN

Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (HER2 negative) breast cancer. Thirteen of 79 unselected very young patients were BRCA1/2 germline mutation carriers. Of the non-BRCA tumors, eight with luminal subtype (HER2 negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were PIK3CA, GATA3, TP53 and MAP2K4. Potential cancer drivers affected in the present non-BRCA tumors include GRHL2, PIK3AP1, CACNA1E, SEMA6D, SMURF2, RSBN1 and MTHFD2. Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1, MUTYH, PALB2, POLD1, POLE, RAD9A, RAD51 and TP53, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.

6.
Nat Commun ; 8(1): 656, 2017 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-28939825

RESUMEN

Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer patients, and identify a median of one mitochondrial single-nucleotide variant (mtSNV) per patient. Some of these mtSNVs occur in recurrent mutational hotspots and associate with aggressive disease. Younger patients have fewer mtSNVs than those who diagnosed at an older age. We demonstrate strong links between mitochondrial and nuclear mutational profiles, with co-occurrence between specific mutations. For example, certain control region mtSNVs co-occur with gain of the MYC oncogene, and these mutations are jointly associated with patient survival. These data demonstrate frequent mitochondrial mutation in prostate cancer, and suggest interplay between nuclear and mitochondrial mutational profiles in prostate cancer.In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.


Asunto(s)
Adenocarcinoma/genética , ADN Mitocondrial/genética , Mutación Puntual , Neoplasias de la Próstata/genética , Adenocarcinoma/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Genes myc , Estudios de Asociación Genética , Genoma Mitocondrial , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Neoplasias de la Próstata/patología , Análisis de Supervivencia
7.
Semin Nephrol ; 35(3): 256-65, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-26215863

RESUMEN

Kidney biopsy is the gold standard procedure for providing diagnostic and prognostic information for patients with glomerular-based diseases, however, the utility of this procedure for assessing longitudinal disease activity is limited. The intense search for noninvasive biomarkers of kidney disease activity and injury is driven in large part by the inherent risks of the kidney biopsy procedure and limited information derived from the morphologic description of biopsy findings. Furthermore, gaps in our understanding of the core intrarenal molecular processes underlying the development and progression of glomerular-based diseases has limited the development of effective targeted therapy. In this review, we discuss the potential utility of molecular analysis of the urine to provide a dynamic window into intrarenal molecular and morphologic responses. We focus on molecular analysis of the urine to identify noninvasive surrogate markers of kidney responses, with the goal of using these biomarkers as more sensitive indicators of progression and tissue-level responses to therapeutic interventions in patients with primary glomerulonephritis.


Asunto(s)
Biomarcadores/análisis , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Riñón/patología , Biopsia , Progresión de la Enfermedad , Humanos , Pronóstico
8.
Nat Genet ; 47(7): 736-45, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26005866

RESUMEN

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.


Asunto(s)
Neoplasias de la Próstata/genética , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , Estudios de Asociación Genética , Heterogeneidad Genética , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Mutación Puntual , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/genética
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