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1.
Cell ; 176(4): 831-843.e22, 2019 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-30735634

RESUMEN

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.


Asunto(s)
Neoplasias de la Próstata/genética , ARN/genética , ARN/metabolismo , Perfilación de la Expresión Génica/métodos , Perfil Genético , Células HEK293 , Humanos , Masculino , MicroARNs/metabolismo , Próstata/metabolismo , Empalme del ARN/genética , ARN Circular , ARN no Traducido/genética , Análisis de Secuencia de ARN/métodos , Transcriptoma
2.
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
3.
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
4.
Blood ; 133(25): 2651-2663, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-30923040

RESUMEN

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.


Asunto(s)
Proteínas Hedgehog/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteína con Dedos de Zinc GLI1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Regulación Leucémica de la Expresión Génica/genética , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Piridinas/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
5.
Nature ; 506(7488): 328-33, 2014 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-24522528

RESUMEN

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.


Asunto(s)
Células Madre Hematopoyéticas/citología , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/citología , Animales , Diferenciación Celular , División Celular , Linaje de la Célula , Células Clonales/citología , Células Clonales/metabolismo , Células Clonales/patología , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Hematopoyesis , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Xenoinjertos , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación/genética , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas Nucleares/genética , Nucleofosmina , Inducción de Remisión , Linfocitos T/metabolismo , Linfocitos T/patología
6.
BMC Cancer ; 18(1): 8, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29295717

RESUMEN

BACKGROUND: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). METHODS: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set. RESULTS: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs. CONCLUSIONS: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement.


Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma Intraductal no Infiltrante/genética , Variaciones en el Número de Copia de ADN , Inestabilidad Genómica , Genómica/métodos , Neoplasias de la Próstata/genética , Adenocarcinoma/patología , Anciano , Carcinoma Intraductal no Infiltrante/patología , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/patología
7.
PLoS Genet ; 7(11): e1002377, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22125496

RESUMEN

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target.


Asunto(s)
Membrana Celular/genética , Epistasis Genética/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Medios de Cultivo , Resistencia a Medicamentos/genética , Escherichia coli/crecimiento & desarrollo , Regulación Bacteriana de la Expresión Génica , Interacción Gen-Ambiente , Proteínas de la Membrana/metabolismo , Redes y Vías Metabólicas/genética , Microscopía Electrónica , Proteínas Asociadas a Microtúbulos/metabolismo , Anotación de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos
8.
Pharm Biol ; 50(4): 490-6, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22136393

RESUMEN

CONTEXT: Praziquantel (PZQ) is the drug available for the treatment of schistosomiasis. The reported reduced cure rates, the failure of treatment after PZQ administration in patients and the existence of resistant parasite strains, reinforce the need to rapidly discover new effective molecules against Schistosoma parasite. OBJECTIVE: To screen the methanol extracts of 79 marine organisms for their schistosomicidal activities against Schistosoma mansoni adult worms in vitro and perform bio-assay directed chromatography for the most active extracts to isolate the active compounds. MATERIALS AND METHODS: Screening of the marine organisms and bio-assay directed chromatography of the most active extracts together with identification of the active isolates using 1D and 2D NMR analysis, were investigated. RESULTS: RESULTS indicated that the isolates echinosides A and B from the sea cucumbers Actinopyga echinites Jaeger and Holothuria polii Delle Chiaie (Holothuriidae) were highly active. Their LC(50) values were equal to 0.19 µg/ml and 0.27 µg/ml, respectively. Detailed (1)HNMR data for echinosides A and B are reported here for the first time. DISCUSSION AND CONCLUSION: These findings demonstrate that the isolated echinosides possess potential in vitro schistosomicidal activity against S. mansoni adult worms. Therefore, echinosides are promising as lead compounds for the development of new schistosomicidal agents.


Asunto(s)
Holoturina/análogos & derivados , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/farmacología , Pepinos de Mar/química , Animales , Bioensayo , Cromatografía , Holothuria , Holoturina/química , Holoturina/aislamiento & purificación , Holoturina/farmacología , Espectroscopía de Resonancia Magnética , Metanol/química , Estructura Molecular , Schistosoma mansoni/crecimiento & desarrollo , Esquistosomicidas/química , Esquistosomicidas/aislamiento & purificación , Solventes/química
9.
Pharm Biol ; 50(2): 134-40, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22338119

RESUMEN

CONTEXT: The cryptolepines originate from the roots of the climbing shrub Cryptolepis sanguinolenta (Lindi) Schitr(Periplocaeae) which is used in Central and West Africa in traditional medicine for the treatment of malaria. OBJECTIVES: Evaluation for the first time of a series of chloro- and aminoalkylamino derivatives of neo- and norneocryptolepines for potential schistosomicidal and molluscicidal activities. MATERIALS AND METHODS: A series of chloro- and aminoalkylamino substituted neo- and norneocryptolepine derivatives were synthesized. They were tested in vitro against viable Schistosoma mansoni Sambon mature worms in culturemedium with fetal serum and antibiotics and in dechlorinated water against the snail vector Biomphalaria alexandrina Ehrenberg. Active compounds were further subjected to determination of their IC50 values. RESULTS: Results showed that six neocryptolepine and two norneocryptolepine derivatives had in vitro schistosomicidal activity on Egyptian and Puerto Rican strains of S. mansoni. The most effective derivative (2-chloro-5-methyl-N-(2-morpholin-4-ethyl)-5H-indolo[2,3b]quinoline-11-amine) has IC50 and IC90 1.26 and 4.05 µM and 3.54 and 6.83 µM with the Egyptian and Puerto Rican strains of Schistosoma, respectively. All eight derivatives showed molluscicidal activity against the vector snail B. alexandrina. The most active compound (2-chloro-11-(4-methylpiperazin-1-yl)-6H-indolo[2,3-b] quinoline) has LC50 0.6 and LC90 3.9 ppm after 24 h. DISCUSSION AND CONCLUSIONS: The findings demonstrate that introducing chloro- and aminoalkylamino side chain initiated both schistosomicidal and molluscicidal activities in these derivatives. The structure­activity relationship of this series of compounds is discussed.


Asunto(s)
Alcaloides/farmacología , Moluscocidas/farmacología , Quinolinas/farmacología , Esquistosomicidas/farmacología , Alcaloides/administración & dosificación , Alcaloides/síntesis química , Animales , Biomphalaria/efectos de los fármacos , Cryptolepis/química , Egipto , Concentración 50 Inhibidora , Dosificación Letal Mediana , Medicinas Tradicionales Africanas , Moluscocidas/administración & dosificación , Moluscocidas/síntesis química , Puerto Rico , Quinolinas/administración & dosificación , Quinolinas/síntesis química , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/administración & dosificación , Esquistosomicidas/síntesis química , Relación Estructura-Actividad , Factores de Tiempo
10.
Pharm Biol ; 50(6): 732-9, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22133013

RESUMEN

CONTEXT: This study is a continuation of our previous work in which a bioassay screening of 346 methanol extracts from 281 Egyptian plant species was carried out for in vitro schistosomicidal activity. OBJECTIVE: Another 309 methanol extracts from 278 plant species were subjected to the bioassay screening using the same technique on viable Schistosoma mansoni Sambon (Schistosomatidae) mature worms in specialized culture medium (Roswell Park Memorial Institute medium 1640) in a trial to discover a source for a schistosomiasis drug from Egyptian flora. MATERIAL AND METHODS: The methanol plant extracts were tested in vitro against viable S. mansoni mature worms in culture medium. Viability of worms was examined after exposure to 100 µg/ml of the extract in the medium for 24 h. Negative (dimethyl sulfoxide) and positive (praziquantel) controls were simultaneously used. Extracts showing schistosomicidal activity were further subjected to determination of their (Lethal concentration) LC50 and LC90 values. RESULTS: Confirmed in vitro antischistosomal activity was found in 42 extracts. Of these, 14 plant species possessed considerably high antischistosomal activity (LC50 ≤ 15 µg/ml), viz. Callistemon viminalis (Soland. Ex Gaertn) Cheel, C. rigidus R.Br., C. speciosus (Sims.) DC, C. citrinus Stapf, Eucalyptus citriodora Hook, E. rostrata Dehnh., Eugenia edulis Vell, E. javanica Lam syn. Syzygium samarangense (Blume) Merril, Melaleuca leucadendron (L.) L., M. stypheloides Sm. (all belong to Myrtaceae), Cryptostegia grandiflora R.Br. (Asclepiadaceae), Zilla spinosa (L.) Prantl (Cruciferae), Ficus trijuja L. (Moraceae) and Fagonia mollis Delile (Zygophylacae). DISCUSSION AND CONCLUSION: These species may represent additional natural sources of bioactive material that deserve further investigation for drug discovery against schistosomiasis.


Asunto(s)
Descubrimiento de Drogas , Extractos Vegetales/farmacología , Plantas/química , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/farmacología , Animales , Egipto , Femenino , Concentración 50 Inhibidora , Masculino , Metanol/química , Myrtaceae/química , Componentes Aéreos de las Plantas/química , Extractos Vegetales/aislamiento & purificación , Schistosoma mansoni/crecimiento & desarrollo , Esquistosomicidas/aislamiento & purificación , Solventes/química
11.
Nat Commun ; 11(1): 4330, 2020 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-32859912

RESUMEN

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.


Asunto(s)
Mutación , Neoplasias/genética , Oncogenes/genética , Caracteres Sexuales , Inestabilidad Cromosómica , Exoma , Femenino , Genoma Humano , Inestabilidad Genómica , Humanos , Modelos Logísticos , Masculino , Sistemas de Lectura Abierta , beta Catenina/genética
12.
Sci Rep ; 9(1): 3590, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30837567

RESUMEN

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data.


Asunto(s)
Puntos de Rotura del Cromosoma , Regulación Neoplásica de la Expresión Génica , Fusión Génica , Proteínas de Fusión Oncogénica , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Transcriptoma , Biomarcadores de Tumor/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Clasificación del Tumor
13.
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
14.
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
15.
Oncotarget ; 6(31): 31693-701, 2015 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-26372731

RESUMEN

Chromosome instability (CIN) in solid tumours results in multiple numerical and structural chromosomal aberrations and is associated with poor prognosis in multiple tumour types. Recent evidence demonstrated CEP17 duplication, a CIN marker, is a predictive marker of anthracycline benefit. An analysis of the BR9601 and MA.5 clinical trials was performed to test the role of existing CIN gene expression signatures as predictive markers of anthracycline sensitivity in breast cancer. Univariate analysis demonstrated, high CIN25 expression score was associated with improved distant relapse free survival (DRFS) (HR: 0.74, 95% CI 0.54-0.99, p = 0.046). High tumour CIN70 and CIN25 scores were associated with aggressive clinicopathological phenotype and increased sensitivity to anthracycline therapy compared to low CIN scores. However, in a prospectively planned multivariate analysis only pathological grade, nodal status and tumour size were significant predictors of outcome for CIN25/CIN70. A limited gene signature was generated, patients with low tumour CIN4 scores benefited from anthracycline treatment significantly more than those with high CIN4 scores (HR 0.37, 95% CI 0.20-0.56, p = 0.001). In multivariate analyses the treatment by marker interaction for CIN4/anthracyclines demonstrated hazard ratio of 0.35 (95% CI 0.15-0.80, p = 0.012) for DRFS. This data shows CIN4 is independent predictor of anthracycline benefit for DRFS in breast cancer.


Asunto(s)
Antraciclinas/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Recurrencia Local de Neoplasia/genética , Transducción de Señal/genética , Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Inestabilidad Cromosómica , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia
16.
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
17.
Can J Ophthalmol ; 49(1): 96-101, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24513365

RESUMEN

OBJECTIVE: To assess how the University of Toronto Visiting Professors Rounds Series (UTVPRS) influenced the knowledge, perceptions, and clinical decision making of Canadian ophthalmologists. DESIGN: Longitudinal cross-sectional. PARTICIPANTS: Eight hundred and fifty ophthalmologists registered with the Canadian Ophthalmological Society. METHODS: Online surveys, using multiple-choice and reflection questions, were administered before and after online viewing of the University of Toronto Ophthalmology grand rounds as screencasts. RESULTS: At 18 months, 124 users registered and watched 429 screencasts. Most participants found UTVPRS to be organized and user friendly. Mean prescreencast correct scores were 1008 versus 1288 postscreencast (p = 0.002). Postscreencast, 73% of participants replied in favour of changing future practice. CONCLUSIONS: UTVPRS was well received with demonstrated knowledge gain and potential practice change. The long-term and patient-related outcomes of the results require further research.


Asunto(s)
Competencia Clínica/estadística & datos numéricos , Instrucción por Computador , Educación Médica Continua/estadística & datos numéricos , Oftalmología/educación , Rondas de Enseñanza/estadística & datos numéricos , Centros Médicos Académicos , Estudios Transversales , Toma de Decisiones , Evaluación Educacional , Estudios de Seguimiento , Encuestas de Atención de la Salud , Conocimientos, Actitudes y Práctica en Salud , Humanos , Ontario , Sociedades Médicas
18.
J Egypt Soc Parasitol ; 44(2): 373-80, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25597151

RESUMEN

During parasitological examination of Biomphalaria pfeifferi snails obtained from Niger state (Nigeria), 2 new types of cercariae were found. They are identified to the level of referring to the major group and described here for the first time. They were examined viable and stained with vital stains as well as fixed in 70% alcohol. They were drawn with a camera lucida and photographed. They are identified as an echinostome cercaria and a xiphidiocercaria. The echinostome is characterized by having a ventral sucker almost double in size the oral one. It has a semicircular structure located beyond the oral sucker. Three pairs of penetration glands are found at the anterior portion of the body. The number of collar spines is relatively large (44-46). The flame cellsare 17 x 2 in number. Two main lateral excretory ducts extend anteriorly, form two typical echinostome loops then pass posteriorly to open together in a diverticulated excretory vesicle. Its tail is relatively long and flattened with 3 fin folds. The tail (640 µm) is longer than the body (475 µm). The xiphidiocercaria belongs to the "ornatae" group. It is relatively small (180.5 x 110 µm) with a long stylet (30 µm). Its oral sucker is one and half times the size of the ventral sucker. Two excretory ducts extend posteriorly in both sides and become dilated and unite to open in a circular excretoryvesicle. Tail is slender shorter than the body and has a dorso-ventral fin fold.


Asunto(s)
Biomphalaria/parasitología , Cercarias/clasificación , Echinostoma/anatomía & histología , Echinostoma/clasificación , Animales , Nigeria
19.
J Egypt Soc Parasitol ; 43(2): 315-25, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24260810

RESUMEN

This study was performed in water ditches under simulated natural conditions in Egypt to elucidate the effect of various environmental factors on Schistosoma mansoni cercarial host location and infection of the definitive host (using albino mice). Evaluation of these factors was dependent on both infection rate of exposed mice as well as the schistosome worm load under the same experimental conditions. The seasonal water temperature proved to be a very important factor and this was proven by the infection rate of mice and the worm load recovered were lower in January and April (16 degrees C and 22 degrees C midday water temperature) and much higher in July and October (29 degrees C and 25 degrees C). The daytime factor is similarly important as temperature illustrated by the schistosome infection of mice groups exposed at 8-10 am was much higher than in groups exposed between 1 pm and 3pm (p < 0.001). The greatest infection rate of mice and worm load were obtained when the shedding snails were close to the exposed group of mice. Both criteria increased with the increase of cercarial density in the water. The length of exposure period is also an extremely important factor for schistosome infection, being highest 87.5% (p < 0.001) in3 hours exposure period. Infection rate was found to be 88.2% and 55.6% of shedding snails were located at water surface and midway to the bottom, respectively, and no infection occurred when located at the bottom. The schistosome infection of mice decreased in presence of increasing density of the floating plant Eichhornia crassipes in the ditch water, but low condensation of the submersed plant Ceratophyllum demersum appeared to have stimulating effect.


Asunto(s)
Biomphalaria/parasitología , Ecosistema , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/parasitología , Animales , Egipto/epidemiología , Humanos , Ratones , Modelos Biológicos , Esquistosomiasis mansoni/epidemiología , Estaciones del Año , Temperatura , Agua
20.
Asian Pac J Trop Biomed ; 3(4): 267-72, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23620849

RESUMEN

OBJECTIVE: To test Candonocypris novaezelandiae (Baird) (C. novaezelandiae), sub-class Ostracoda, obtained from the Nile, Egypt for its predatory activity on snail, Biomphalaria alexandrina (B. alexandrina), intermediate host of Schistosoma mansoni (S. mansoni) and on the free-living larval stages of this parasite (miracidia and cercariae). METHODS: The predatory activity of C. novaezelandiae was determined on B. alexandrina snail (several densities of eggs, newly hatched and juveniles). This activity was also determined on S. mansoni miracidia and cercariae using different volumes of water and different numbers of larvae. C. novaezelandiae was also tested for its effect on infection of snails and on the cercarial production. RESULTS: C. novaezelandiae was found to feed on the eggs, newly hatched and juvenile snails, but with significant reduction in the consumption in the presence of other diet like the blue green algae (Nostoc muscorum). This ostracod also showed considerable predatory activity on the free-living larval stages of S. mansoni which was affected by certain environmental factors such as volume of water, density of C. novaezelandiae and number of larvae of the parasite. CONCLUSIONS: The presence of this ostracod in the aquatic habitat led to significant reduction of snail population, infection rate of snails with schistosme miracidia as well as of cercarial production from the infected snails. This may suggest that introducing C. novaezelandiae into the habitat at schistosome risky sites could suppress the transmission of the disease.


Asunto(s)
Crustáceos/fisiología , Control Biológico de Vectores , Control de Plagas , Schistosoma mansoni , Esquistosomiasis mansoni/prevención & control , Esquistosomiasis mansoni/transmisión , Animales , Conducta Predatoria
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