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Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

机译:全基因组测序揭示复发性急性髓细胞白血病的克隆进化

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摘要

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level1'2. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
机译:大多数急性髓细胞性白血病(AML)患者在复发后死于进行性疾病,这与细胞遗传学水平上的克隆进化相关[1] 2。为了确定与复发相关的突变谱,我们对八名AML患者的原发肿瘤和复发基因组进行了测序,并使用深度测序验证了数百种体细胞突变。这使我们能够准确地在复发时定义克隆性和克隆进化模式。除了在AML中发现新颖的,反复突变的基因(例如WAC,SMC3,DIS3,DDX41和DAXX)外,我们还发现了AML复发期间两个主要的克隆进化模式:(1)原发肿瘤中的始发克隆获得了突变并进化为复发性克隆,或(2)建立克隆的亚克隆在初始治疗后仍然存活,获得了更多的突变并在复发时扩展。在所有情况下,化学疗法都无法根除建立的克隆。在所有八例病例中,对复发特异性突变与原发性肿瘤突变的比较表明,转化率增加了,这可能是由于细胞毒性化学疗法引起的DNA损伤。这些数据表明,AML复发与新突变和克隆进化的增加有关,这部分是由患者接受的建立和维持缓解的化学疗法所致。

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  • 来源
    《Nature》 |2012年第7382期|p.506-510|共5页
  • 作者单位

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    Division of Biostatistics, Washington University, St Louis, Missouri 63110, USA;

    Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Genetics, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.,Department of Pathology and Immunology, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    The Genomelnstitute, Washington University, St Louis, Missouri 63108, USA.,Department of Genetics, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.;

    Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.,Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA;

  • 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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