DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.
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DOI：
10.1038/nature07485
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发表时间：
2008-11-06
期刊：
影响因子：
64.8
通讯作者：
Wilson, Richard K.
中科院分区：
文献类型：
--
作者：
Ley, Timothy J.;Mardis, Elaine R.;Ding, Li;Fulton, Bob;McLellan, Michael D.;Chen, Ken;Dooling, David;Dunford-Shore, Brian H.;McGrath, Sean;Hickenbotham, Matthew;Cook, Lisa;Abbott, Rachel;Larson, David E.;Koboldt, Dan C.;Pohl, Craig;Smith, Scott;Hawkins, Amy;Abbott, Scott;Locke, Devin;Hillier, LaDeana W.;Miner, Tracie;Fulton, Lucinda;Magrini, Vincent;Wylie, Todd;Glasscock, Jarret;Conyers, Joshua;Sander, Nathan;Shi, Xiaoqi;Osborne, John R.;Minx, Patrick;Gordon, David;Chinwalla, Asif;Zhao, Yu;Ries, Rhonda E.;Payton, Jacqueline E.;Westervelt, Peter;Tomasson, Michael H.;Watson, Mark;Baty, Jack;Ivanovich, Jennifer;Heath, Sharon;Shannon, William D.;Nagarajan, Rakesh;Walter, Matthew J.;Link, Daniel C.;Graubert, Timothy A.;DiPersio, John F.;Wilson, Richard K.
急性髓样白血病是一种高度恶性的造血肿瘤，在过去的二十年中，每年都会影响约13,000名成年人现在可以以合理的成本和时间框架来利用这种方法来无偏见的肿瘤特异性体细胞突变，从而改变蛋白质编码基因。我们通过测序典型的急性髓样白血病基因组及其匹配的正常对应物，从患者的皮肤中获得了10个基因。我们在表现和继电器中几乎所有肿瘤细胞中都存在新的突变，其功能尚不清楚。测序是一种无偏见的方法，可以发现癌症基因组中的突变，并鉴定可能对靶向疗法有反应的新基因。
我们使用大量平行的测序技术来对肿瘤和正常皮肤细胞的基因组DNA进行典型呈现的患者，并具有正常细胞遗传学的Fab M1急性髓样白血病（AML）。 2,647,695个良好支持的单核苷酸在肿瘤基因组中发现的变体（SNV），在患者的皮肤基因组中也检测到2,588,486（97.7％），这限制了需要进一步研究的变体数量，我们将我们的下游分析限制为编码。注释基因的序列：我们发现整个基因组中的八个杂合，非同义体细胞SNV。成员（CDH24和PCLKC），G蛋白偶联受体（GPR123和EBI2），一种蛋白质磷酸酶（PTPRT），潜在的鸟嘌呤核交换因子（KNDC1），肽/药物转运蛋白（SLC15A1）以及Glutamate受体基因Grinl1b）。它们在介绍中几乎所有肿瘤细胞中都呈现，并在11个月后再次在中继中呈现，这表明患者具有一个主要的克隆，其中包含所有突变。
Acute myeloid leukemia is a highly malignant hematopoietic tumor that affects about 13,000 adults yearly in the United States. The treatment of this disease has changed little in the past two decades, since most of the genetic events that initiate the disease remain undiscovered. Whole genome sequencing is now possible at a reasonable cost and timeframe to utilize this approach for unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes. Here we show the results obtained by sequencing a typical acute myeloid leukemia genome and its matched normal counterpart, obtained from the patient’s skin. We discovered 10 genes with acquired mutations; two were previously described mutations thought to contribute to tumor progression, and 8 were novel mutations present in virtually all tumor cells at presentation and relapse, whose function is not yet known. Our study establishes whole genome sequencing as an unbiased method for discovering initiating mutations in cancer genomes, and for identifying novel genes that may respond to targeted therapies. We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical presentation of FAB M1 Acute Myeloid Leukemia (AML) with normal cytogenetics. 32.7-fold ‘haploid’ coverage (98 billion bases) was obtained for the tumor genome, and 13.9-fold coverage (41.8 billion bases) was obtained for the normal sample. Of 2,647,695 well-supported Single Nucleotide Variants (SNVs) found in the tumor genome, 2,588,486 (97.7%) also were detected in the patient’s skin genome, limiting the number of variants that required further study. For the purposes of this initial study, we restricted our downstream analysis to the coding sequences of annotated genes: we found only eight heterozygous, non-synonymous somatic SNVs in the entire genome. All were novel, including mutations in protocadherin/cadherin family members (CDH24 and PCLKC), G-protein coupled receptors (GPR123 and EBI2), a protein phosphatase (PTPRT), a potential guanine nucleotide exchange factor (KNDC1), a peptide/drug transporter (SLC15A1), and a glutamate receptor gene (GRINL1B). We also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. Based on deep readcount data, we determined that all of these mutations (except FLT3) were present in nearly all tumor cells at presentation, and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. These results demonstrate the power of whole genome sequencing to discover novel cancer-associated mutations.
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