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DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.
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.
Authors : 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 ,
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[28318150] Expression of CD4 is correlated with an unfavorable prognosis in wild-type NPM1, FLT3-ITD-negative cytogenetically normal adult acute myeloid leukemia.
[28003272] Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia.
[27821287] Combination of RNA- and exome sequencing: Increasing specificity for identification of somatic point mutations and indels in acute leukaemia.
[27016502] DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.
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[26227220] Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia.
[26177509] Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.
[25648021] NPM1 gene mutation in Egyptian patients with cytogenetically normal acute myeloid leukemia.
[24659319] The use of molecular genetics to refine prognosis in acute myeloid leukemia.
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