排序方式: 共有14条查询结果,搜索用时 15 毫秒
1.
Whole‐exome DNA sequence analysis of Brca2‐ and Trp53‐deficient mouse mammary gland tumours
下载免费PDF全文
![点击此处可从《The Journal of pathology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jeffrey C Francis James Campbell Wenbin Wei Javier Armisen‐Garrido Ioannis Assiotis Lina Chen Iwanka Kozarewa Kerry Fenwick Amanda Swain Christopher J Lord Alan Ashworth 《The Journal of pathology》2015,236(2):186-200
Germline mutations in the tumour suppressor BRCA2 predispose to breast, ovarian and a number of other human cancers. Brca2‐deficient mouse models are used for preclinical studies but the pattern of genomic alterations in these tumours has not yet been described in detail. We have performed whole‐exome DNA sequencing analysis of mouse mammary tumours from Blg–Cre Brca2f/f Trp53f/f animals, a model of BRCA2‐deficient human cancer. We also used the sequencing data to estimate DNA copy number alterations in these tumours and identified a recurrent copy number gain in Met, which has been found amplified in other mouse mammary cancer models. Through a comparative genomic analysis, we identified several mouse Blg–Cre Brca2f/f Trp53f/f mammary tumour somatic mutations in genes that are also mutated in human cancer, but few of these genes have been found frequently mutated in human breast cancer. A more detailed analysis of these somatic mutations revealed a set of genes that are mutated in human BRCA2 mutant breast and ovarian tumours and that are also mutated in mouse Brca2‐null, Trp53‐null mammary tumours. Finally, a DNA deletion surrounded by microhomology signature found in human BRCA1/2‐deficient cancers was not common in the genome of these mouse tumours. Although a useful model, there are some differences in the genomic landscape of tumours arising in Blg–Cre Brca2f/f Trp53f/f mice compared to human BRCA‐mutated breast cancers. Therefore, this needs to be taken into account in the use of this model. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
2.
3.
D Leongamornlert E Saunders T Dadaev M Tymrakiewicz C Goh S Jugurnauth-Little I Kozarewa K Fenwick I Assiotis D Barrowdale K Govindasami M Guy E Sawyer R Wilkinson The UKGPCS Collaborators A C Antoniou R Eeles Z Kote-Jarai 《British journal of cancer》2014,110(6):1663-1672
Background:
Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated.Methods:
Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified.Results:
We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56–2.42).Conclusions:
These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread. 相似文献4.
Caterina Marchiò Salvatore Piscuoglio Charlotte KY Ng Patty Wai Maryou B Lambros Eleftherios P Samartzis Konstantin J Dedes Jessica Frankum Ilirjana Bajrami Alicja Kopec Alan Mackay Roger A'hern Kerry Fenwick Iwanka Kozarewa Jarle Hakas Costas Mitsopoulos David Hardisson Christopher J Lord Chandan Kumar‐Sinha Alan Ashworth Britta Weigelt Anna Sapino Arul M Chinnaiyan Christopher A Maher Jorge S Reis‐Filho 《The Journal of pathology》2014,232(5):553-565
5.
Natrajan R Mackay A Lambros MB Weigelt B Wilkerson PM Manie E Grigoriadis A A'hern R van der Groep P Kozarewa I Popova T Mariani O Turajlic S Furney SJ Marais R Rodruigues DN Flora AC Wai P Pawar V McDade S Carroll J Stoppa-Lyonnet D Green AR Ellis IO Swanton C van Diest P Delattre O Lord CJ Foulkes WD Vincent-Salomon A Ashworth A Henri Stern M Reis-Filho JS 《The Journal of pathology》2012,227(1):29-41
6.
Iorns E Ward TM Dean S Jegg A Thomas D Murugaesu N Sims D Mitsopoulos C Fenwick K Kozarewa I Naceur-Lombarelli C Zvelebil M Isacke CM Lord CJ Ashworth A Hnatyszyn HJ Pegram M Lippman M 《Breast cancer research and treatment》2012,135(1):79-91
Cancer is caused by mutations in oncogenes and tumor suppressor genes, resulting in the deregulation of processes fundamental to the normal behavior of cells. The identification and characterization of oncogenes and tumor suppressors has led to new treatment strategies that have significantly improved cancer outcome. The advent of next generation sequencing has allowed the elucidation of the fine structure of cancer genomes, however, the identification of pathogenic changes is complicated by the inherent genomic instability of cancer cells. Therefore, functional approaches for the identification of novel genes involved in the initiation and development of tumors are critical. Here we report the first whole human genome in vivo RNA interference screen to identify functionally important tumor suppressor genes. Using our novel approach, we identify previously validated tumor suppressor genes including TP53 and MNT, as well as several novel candidate tumor suppressor genes including leukemia inhibitory factor receptor (LIFR). We show that LIFR is a key novel tumor suppressor, whose deregulation may drive the transformation of a significant proportion of human breast cancers. These results demonstrate the power of genome wide in vivo RNAi screens as a method for identifying novel genes regulating tumorigenesis. 相似文献
7.
Walker BA Wardell CP Melchor L Hulkki S Potter NE Johnson DC Fenwick K Kozarewa I Gonzalez D Lord CJ Ashworth A Davies FE Morgan GJ 《Blood》2012,120(5):1077-1086
We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111. 相似文献
8.
Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen 总被引:1,自引:0,他引:1
Mendes-Pereira AM Sims D Dexter T Fenwick K Assiotis I Kozarewa I Mitsopoulos C Hakas J Zvelebil M Lord CJ Ashworth A 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(8):2730-2735
Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment. 相似文献
9.
Louise J Barber Shahneen Sandhu Lina Chen James Campbell Iwanka Kozarewa Kerry Fenwick Ioannis Assiotis Daniel Nava Rodrigues Jorge S Reis-Filho Victor Moreno Joaquin Mateo L Rhoda Molife Johann De Bono Stan Kaye Christopher J Lord Alan Ashworth 《The Journal of pathology》2013,229(3):422-429
PARP inhibitors (PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment‐naive and post‐olaparib treatment biopsies identified tumour‐specific BRCA2 secondary mutations in olaparib‐resistant metastases. These secondary mutations restored full‐length BRCA2 protein, and most likely cause olaparib resistance by re‐establishing BRCA2 function in the tumour cells. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
10.
Irene Y Chong David Cunningham Louise J Barber James Campbell Lina Chen Iwanka Kozarewa Kerry Fenwick Ioannis Assiotis Sebastian Guettler Isaac Garcia‐Murillas Saima Awan Maryou Lambros Naureen Starling Andrew Wotherspoon Gordon Stamp David Gonzalez‐de‐Castro Martin Benson Ian Chau Sanna Hulkki Mahrokh Nohadani Zakaria Eltahir Alina Lemnrau Nicholas Orr Sheela Rao Christopher J Lord Alan Ashworth 《The Journal of pathology》2013,231(3):301-310
The incidence of oesophagogastric junctional (OGJ) adenocarcinoma is rising rapidly in western countries, in contrast to the declining frequency of distal gastric carcinoma. Treatment options for adenocarcinomas involving the oesophagogastric junction are limited and the overall prognosis is extremely poor. To determine the genomic landscape of OGJ adenocarcinoma, exomes of eight tumours and matched germline DNA were subjected to massively parallel DNA sequencing. Microsatellite instability was observed in three tumours which coincided with an elevated number of somatic mutations. In total, 117 genes were identified that had predicted coding alterations in more than one tumour. Potentially actionable coding mutations were identified in 67 of these genes, including those in CR2, HGF, FGFR4, and ESRRB. Twenty‐nine genes harbouring somatic coding mutations and copy number changes in the MSS OGJ dataset are also known to be altered with similar predicted functional consequence in other tumour types. Compared with the published mutational profile of gastric cancers, 49% (57/117) of recurrently mutated genes were unique to OGJ tumours. TP53, SYNE1, and ARID1A were amongst the most frequently mutated genes in a larger OGJ cohort. Our study provides an insight into the mutational landscape of OGJ adenocarcinomas and confirms that this is a highly mutated and heterogeneous disease. Furthermore, we have uncovered somatic mutations in therapeutically relevant genes which may represent candidate drug targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献