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Ley TJ Mardis ER Ding L Fulton B McLellan MD Chen K Dooling D Dunford-Shore BH McGrath S Hickenbotham M Cook L Abbott R Larson DE Koboldt DC Pohl C Smith S Hawkins A Abbott S Locke D Hillier LW Miner T Fulton L Magrini V Wylie T Glasscock J Conyers J Sander N Shi X Osborne JR Minx P Gordon D Chinwalla A Zhao Y Ries RE Payton JE Westervelt P Tomasson MH Watson M Baty J Ivanovich J Heath S Shannon WD Nagarajan R Walter MJ Link DC Graubert TA DiPersio JF Wilson RK 《Nature》2008,456(7218):66-72
Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies. 相似文献
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Ding L Ley TJ Larson DE Miller CA Koboldt DC Welch JS Ritchey JK Young MA Lamprecht T McLellan MD McMichael JF Wallis JW Lu C Shen D Harris CC Dooling DJ Fulton RS Fulton LL Chen K Schmidt H Kalicki-Veizer J Magrini VJ Cook L McGrath SD Vickery TL Wendl MC Heath S Watson MA Link DC Tomasson MH Shannon WD Payton JE Kulkarni S Westervelt P Walter MJ Graubert TA Mardis ER Wilson RK DiPersio JF 《Nature》2012,481(7382):506-510
Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. 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. 相似文献
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