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Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome BackgroundThe full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.MethodsWe used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome.ResultsWe identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis.ConclusionsBy comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The New England Journal of Medicine The New England Journal of Medicine

Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

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References (31)

Publisher
The New England Journal of Medicine
Copyright
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
ISSN
0028-4793
eISSN
1533-4406
DOI
10.1056/NEJMoa0903840
pmid
19657110
Publisher site
See Article on Publisher Site

Abstract

BackgroundThe full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.MethodsWe used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome.ResultsWe identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis.ConclusionsBy comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.

Journal

The New England Journal of Medicine – The New England Journal of Medicine

Published: Sep 10, 2009

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