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Whole genomes redefine the mutational landscape of pancreatic cancer

机译:全基因组重新定义了胰腺癌的突变格局

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摘要

Pancreatic cancr remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.%对100个胰腺导管腺癌样本所做的一项全基因组测序分析,显示了胰腺癌变的已知和新发现的基因驱动因素。这些基因改变可根据结构变化的模式被分成四个子类型——稳定型、局部重排型、分散型和不稳定型,从而提出了在临床治疗中提高定位准确度的可能性。若干种肿瘤都存在局部扩增,其中很多含有可以用药物处理的致癌基因,尽管每个出现的频率都比较低。基因组不稳定性与DNA维护基因的失活和DNA损伤修复缺陷的一个突变特征同时出现。在一项概念证明研究中,作者显示了这些基因组特征作为治疗选择的假定生物标记的潜在用途。
机译:胰腺癌仍然是最致命的恶性肿瘤之一,也是主要的健康负担。我们对100例胰腺导管腺癌(PDAC)进行了全基因组测序和拷贝数变异(CNV)分析。导致基因破坏的染色体重排普遍存在,影响已知对胰腺癌重要的基因(TP53,SMAD4,CDKN2A,ARID1A和ROBO2)和胰腺癌发生的新候选驱动因子(KDM6A和PREX2)。结构变化的模式(染色体结构的变化)将PDAC分为4种亚型,具有潜在的临床实用性:这些亚型被称为稳定,局部重排,分散和不稳定。很大一部分含有局灶性扩增,其中许多包含可药物致癌基因(ERBB2,MET,FGFR1,CDK6,PIK3R3和PIK3CA),但患者个体患病率较低。基因组不稳定性与DNA维持基因(BRCA1,BRCA2或PALB2)的失活和DNA损伤修复缺陷的突变特征共同分离。在接受铂金治疗的8位患者中,采用这种有缺陷的DNA维持措施的5位患者中有4位反应了。%对100个糖尿病导管腺癌样本治疗的某一全基因组进行分析,显示出癌变的已知和新发现的基因驱动因素。这些基因改变可根据结构变化的模式被分为四个子类型-稳定型,局部重排型,分散型和可变型,从而提出了在临床治疗中提高定位准确度的可能性。一些种肿瘤都存在局部扩展,其中很多含有很多可以用药物处理的致癌基因,尽管每个出现的频率都比较低。基因组不稳定性与DNA维护基因的失活和DNA损伤修复缺陷的一个突变。特征同时出现。在一项概念证明研究中,作者显示了这些基因组特征作为治疗选择的预先生物标记的潜在用途。

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  • 来源
    《Nature》 |2015年第7540期|495-501a3|共8页
  • 作者单位

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia;

    The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia, St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia;

    The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia, Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK;

    Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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