Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome
Elaine R. Mardis, Ph.D., Li Ding, Ph.D., David J. Dooling, Ph.D., David E. Larson, Ph.D., Michael D. McLellan, B.S., Ken Chen, Ph.D., Daniel C. Koboldt, M.S., Robert S. Fulton, M.S., Kim D. Delehaunty, B.A., Sean D. McGrath, M.S., Lucinda A. Fulton, M.S., Devin P. Locke, Ph.D., Vincent J. Magrini, Ph.D., Rachel M. Abbott, B.S., Tammi L. Vickery, B.S., Jerry S. Reed, M.S., Jody S. Robinson, M.S., Todd Wylie, B.S., Scott M. Smith, Lynn Carmichael, B.S., James M. Eldred, Christopher C. Harris, B.S., Jason Walker, B.A., B.S., Joshua B. Peck, M.B.A., Feiyu Du, M.S., Adam F. Dukes, B.A., Gabriel E. Sanderson, B.S., Anthony M. Brummett, Eric Clark, Joshua F. McMichael, B.S., Rick J. Meyer, M.S., Jonathan K. Schindler, B.S., B.A., Craig S. Pohl, M.S., John W. Wallis, Ph.D., Xiaoqi Shi, M.S., Ling Lin, M.S., Heather Schmidt, B.S., Yuzhu Tang, M.D., Carrie Haipek, M.S., Madeline E. Wiechert, M.S., Jolynda V. Ivy, M.B.A., Joelle Kalicki, B.S., Glendoria Elliott, Rhonda E. Ries, M.A., Jacqueline E. Payton, M.D., Ph.D., Peter Westervelt, M.D., Ph.D., Michael H. Tomasson, M.D., Mark A. Watson, M.D., Ph.D., Jack Baty, B.A., Sharon Heath, William D. Shannon, Ph.D., Rakesh Nagarajan, M.D., Ph.D., Daniel C. Link, M.D., Matthew J. Walter, M.D., Timothy A. Graubert, M.D., John F. DiPersio, M.D., Ph.D., Richard K. Wilson, Ph.D., and Timothy J. Ley, M.D.
Background The full complement of DNA mutations that are responsiblefor the pathogenesis of acute myeloid leukemia (AML) is notyet known.
Methods We used massively parallel DNA sequencing to obtaina very high level of coverage (approximately 98%) of a primary,cytogenetically normal, de novo genome for AML with minimalmaturation (AML-M1) and a matched normal skin genome.
Results We identified 12 acquired (somatic) mutations withinthe coding sequences of genes and 52 somatic point mutationsin conserved or regulatory portions of the genome. All mutationsappeared to be heterozygous and present in nearly all cellsin the tumor sample. Four of the 64 mutations occurred in atleast 1 additional AML sample in 188 samples that were tested.Mutations in NRAS and NPM1 had been identified previously inpatients with AML, but two other mutations had not been identified.One of these mutations, in the IDH1 gene, was present in 15of 187 additional AML genomes tested and was strongly associatedwith normal cytogenetic status; it was present in 13 of 80 cytogeneticallynormal samples (16%). The other was a nongenic mutation in agenomic region with regulatory potential and conservation inhigher mammals; we detected it in one additional AML tumor.The AML genome that we sequenced contains approximately 750point mutations, of which only a small fraction are likely tobe relevant to pathogenesis.
Conclusions By comparing the sequences of tumor and skin genomesof a patient with AML-M1, we have identified recurring mutationsthat may be relevant for pathogenesis.
Source Information
From the Departments of Genetics (E.R.M., L.D., V.J.M., R.K.W., T.J.L.), Medicine (R.E.R., P.W., M.H.T., S.H., W.D.S., D.C.L., M.J.W., T.A.G., J.F.D., T.J.L.), and Pathology and Immunology (J.E.P., M.A.W., R.N.); the Genome Center (E.R.M., L.D., D.J.D., D.E.L., M.D.M., K.C., D.C.K., R.S.F., K.D.D., S.D.M., L.A.F., D.P.L., V.J.M., R.M.A., T.L.V., J.S. Reed, J.S. Robinson, T.W., S.M.S., L.C., J.M.E., C.C.H., J.W., J.B.P., F.D., A.F.D., G.E.S., A.M.B., E.C., J.F.M., R.J.M., J.K.S., C.S.P., J.W.W., X.S., L.L., H.S., Y.T., C.H., M.E.W., J.V.I., J.K., G.E., M.A.W., R.K.W., T.J.L.); Siteman Cancer Center (P.W., M.H.T., M.A.W., S.H., W.D.S., R.N., D.C.L., M.J.W., T.A.G., J.F.D., R.K.W., T.J.L.); and the Division of Biostatistics (J.B.) — all at Washington University, St. Louis. This article (10.1056/NEJMoa0903840) was published on August 5, 2009, at NEJM.org.
Address reprint requests to Dr. Ley at Washington University, 660 S. Euclid Ave., Campus Box 8007, St. Louis, MO 63110, or at timley{at}wustl.edu.
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