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1.
J Math Biol ; 72(1-2): 47-86, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25833184

RESUMEN

Breakage-fusion-bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then 'unfolds' into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. Here we study the evolution space of breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are [Formula: see text] qualitatively distinct evolutions involving [Formula: see text] breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the process to show these evolutions are not equally likely, and also describe how amplicons become localized. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples.


Asunto(s)
Roturas del ADN , Evolución Molecular , Modelos Genéticos , Ciclo Celular/genética , Replicación del ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Humanos , Conceptos Matemáticos , Modelos Moleculares , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Conformación de Ácido Nucleico , Procesos Estocásticos
2.
Br J Cancer ; 104(2): 361-8, 2011 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-21063398

RESUMEN

BACKGROUND: Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown. METHODS: To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment. RESULTS: Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression. CONCLUSION: Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome.


Asunto(s)
Antineoplásicos/uso terapéutico , Heterogeneidad Genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Terapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia
3.
Sci Rep ; 9(1): 10686, 2019 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-31337860

RESUMEN

Activation of cell cycle regulated transcription during the G1-to-S transition initiates S phase entry and cell cycle commitment. The molecular mechanisms involving G1/S transcriptional regulation are well established and have been shown to be evolutionary conserved from yeast to humans. Previous work has suggested that changes to the chromatin state, specifically through histone acetylation, has an important role in the regulation of G1/S transcription in both yeast and human cells. Here we investigate the role of histone acetylation in G1/S transcriptional regulation in the budding yeast Saccharomyces cerevisiae. Our work shows that histone acetylation at specific sites at G1/S target gene promoters peaks at the G1-to-S transition, coinciding with their peak transcription levels. Acetylation at G1/S target promoters is significantly reduced upon deletion of the previously implicated histone acetyltransferase Gcn5, but G1/S cell cycle regulated transcription is largely unaffected. The histone deacetylase Rpd3, suggested to have a role in Whi5-dependent repression, is required for full repression of G1/S target genes in the G1 and S phases. However, in the context of transcriptionally active levels during the G1-to-S transition, this seems to play a minor role in the regulation of cell cycle transcription. Our data suggests that histone acetylation might modulate the amplitude of G1/S cell cycle regulated transcription in Saccharomyces cerevisiae, but has a limited role in its overall regulation.


Asunto(s)
Ciclo Celular/fisiología , Regulación Fúngica de la Expresión Génica , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Acetilación , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Histona Acetiltransferasas/genética , Histona Desacetilasas/genética , Regiones Promotoras Genéticas , Fase S/fisiología , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética
4.
Oncogene ; 25(41): 5693-706, 2006 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-16636668

RESUMEN

The short arm of chromosome 8, 8p, is often rearranged in carcinomas, typically showing distal loss by unbalanced translocation. We analysed 8p rearrangements in 48 breast, pancreatic and colon cancer cell lines by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization, with a tiling path of 0.2 Mb resolution over 8p12 and 1 Mb resolution over chromosome 8. Selected breast lines (MDA-MB-134, MDA-MB-175, MDA-MB-361, T-47D and ZR-75-1) were analysed further. Most cell lines showed loss of 8p distal to a break that was between 31 Mb (5' to NRG1) and the centromere, but the translocations were accompanied by variable amplifications, deletions and inversions proximal to this break. The 8p12 translocation in T-47D was flanked by an inversion of 4 Mb, with a 100 kb deletion at the proximal end. The dicentric t(8;11) in ZR-75-1 carries multiple rearrangements including interstitial deletions, a triplicated translocation junction between NRG1 and a fragment of 11q (unconnected to CCND1), and two separate amplifications, of FGFR1 and CCND1 . We conclude that if there is a tumour suppressor gene on 8p it may be near 31 Mb, for example WRN; but the complexity of 8p rearrangements suggests that they target various genes proximal to 31 Mb including NRG1 and the amplicon centred around ZNF703/FLJ14299.


Asunto(s)
Neoplasias de la Mama/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 8 , Neoplasias del Colon/genética , Neoplasias Pancreáticas/genética , Línea Celular Tumoral , Cromosomas Artificiales Bacterianos , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Hibridación de Ácido Nucleico
6.
Oncogene ; 29(35): 4905-13, 2010 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-20581869

RESUMEN

Resistance to chemotherapy in ovarian cancer is poorly understood. Evolutionary models of cancer predict that, following treatment, resistance emerges either because of outgrowth of an intrinsically resistant sub-clone or evolves in residual disease under the selective pressure of treatment. To investigate genetic evolution in high-grade serous (HGS) ovarian cancers, we first analysed cell line series derived from three cases of HGS carcinoma before and after platinum resistance had developed (PEO1, PEO4 and PEO6; PEA1 and PEA2; and PEO14 and PEO23). Analysis with 24-colour fluorescence in situ hybridisation and single nucleotide polymorphism (SNP) array comparative genomic hybridisation (CGH) showed mutually exclusive endoreduplication and loss of heterozygosity events in clones present at different time points in the same individual. This implies that platinum-sensitive and -resistant disease was not linearly related, but shared a common ancestor at an early stage of tumour development. Array CGH analysis of six paired pre- and post-neoadjuvant treatment HGS samples from the CTCR-OV01 clinical study did not show extensive copy number differences, suggesting that one clone was strongly dominant at presentation. These data show that cisplatin resistance in HGS carcinoma develops from pre-existing minor clones but that enrichment for these clones is not apparent during short-term chemotherapy treatment.


Asunto(s)
Evolución Molecular , Heterogeneidad Genética , Genómica/métodos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , Hibridación Genómica Comparativa , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/tratamiento farmacológico , Factores de Tiempo
7.
Oncogene ; 27(23): 3345-59, 2008 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-18084325

RESUMEN

Chromosome translocations in the common epithelial cancers are abundant, yet little is known about them. They have been thought to be almost all unbalanced and therefore dismissed as mostly mediating tumour suppressor loss. We present a comprehensive analysis by array painting of the chromosome translocations of breast cancer cell lines HCC1806, HCC1187 and ZR-75-30. In array painting, chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays. A total of 200 breakpoints were identified and all were mapped to 1 Mb resolution on bacterial artificial chromosome (BAC) arrays, then 40 selected breakpoints, including all balanced breakpoints, were further mapped on tiling-path BAC arrays or to around 2 kb resolution using oligonucleotide arrays. Many more of the translocations were balanced at 1 Mb resolution than expected, either reciprocal (eight in total) or balanced for at least one participating chromosome (19 paired breakpoints). Second, many of the breakpoints were at genes that are plausible targets of oncogenic translocation, including balanced breaks at CTCF, EP300/p300 and FOXP4. Two gene fusions were demonstrated, TAX1BP1-AHCY and RIF1-PKD1L1. Our results support the idea that chromosome rearrangements may play an important role in common epithelial cancers such as breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Rotura Cromosómica , Pintura Cromosómica/métodos , Genes Relacionados con las Neoplasias , Análisis de Matrices Tisulares/métodos , Translocación Genética , Línea Celular Tumoral , Mapeo Cromosómico/métodos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Genoma Humano , Humanos , Proteínas de la Membrana/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/genética , Oncogenes/fisiología , Proteínas de Unión a Telómeros/genética
8.
Aust N Z J Surg ; 61(8): 636-9, 1991 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1651075

RESUMEN

Malignant fibrous histiocytoma (MFH) is a rare tumour of the spermatic cord. We present the second reported case in Australia and review the literature, discussing the recommended management and prognosis of this condition.


Asunto(s)
Neoplasias de los Genitales Masculinos , Histiocitoma Fibroso Benigno , Cordón Espermático , Anciano , Anciano de 80 o más Años , Neoplasias de los Genitales Masculinos/patología , Histiocitoma Fibroso Benigno/patología , Humanos , Masculino , Cordón Espermático/patología
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