Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

By Elaine R. Mardis, Li Ding, D. Dooling, David E. Larson, M. McLellan, Ken Chen, Daniel C. Koboldt, R. Fulton, K. D. Delehaunty, S. McGrath and 48 more. New England Journal of Medicine, 2009

2,302 citations recorded by the source corpus.

BACKGROUND The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known. METHODS We 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. RESULTS We 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. CONCLUSIONS By 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.

Subfields: Genetics, Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6da37aabffaf8b75ea48030c262b1cc051405c8a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Hematology

In Molecular Biology

Citations in the corpus

The Definition of Primary and Secondary Glioblastoma (2012, background): “Exceptions are central chondrosarcomas (~55%) (16), intrahepatic cholangio-carcinomas (23%) (17), acute myeloid leukemia (AML; 15–20%) (18-23), angioimmunoblastic T-cell lymphoma (AITL; ~20%) (24) malignant melanoma (~10%) (25), and anaplastic thyroid cancer (~10%) (26).”
Targeting Metabolism for Cancer Therapy (2017, background): “A specific inhibitor of mutant IDH2, AG-221 (enasidenib) confers survival benefit in a mouse model of IDH2-mutant AML (Quivoron et al., 2014; Yen et al., 2017) and became the first compound targeting mutant IDH to enter clinical trials in 2014.”
The molecular taxonomy of primary prostate cancer (2015, background): “After further investigating DNA methylation differences between IDH-mutant and wild type tumors among prostate cancers, gliomas, and AMLs, we found that hypermethylated loci were specific to the cancer type rather than IDH mutants (Figure S5F).”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Since then, IDH1 mutations have also been detected in chondrosarcomas, cholangiocarcinomas, colorectal cancer, thyroid cancer, and AML (54).”
Biology, risk stratification, and therapy of pediatric acute leukemias: an update. (2011, background): “Analysis of the second case of cytogenetically normal AML revealed 12 mutations in annotated protein-coding genes or regulatory RNAs and 52 mutations in noncoding regions of the genome.(87) Four genes, NPM1, NRAS, IDH1, and a conserved region on chromosome 10, were found in at least one additional s”
SciClone: Inferring Clonal Architecture and Tracking the Spatial and Temporal Patterns of Tumor Evolution (2014, methodology): “To obtain a more objective view of this sample’s clonal architecture, we identified low-frequency subclones by clustering the VAFs from copy number neutral, LOH-free, non-repetitive regions of the genome using SciClone, which uses an approach based on variational Bayesian beta mixture modeling [43,4”
The origin and evolution of mutations in Acute Myeloid Leukemia (2012, methodology): “By comparing these two subtypes of AML, we were able to distinguish the mutations that are likely to be initiating events in the cytogenetically normal cases, versus the cooperating events that are common to both subtypes; this analysis suggests that mutations in NPM1, DNMT3A, and IDH1 may act as ma”
Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. (2011, background): “[25] Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt”