Recurring mutations found by sequencing an acute myeloid leukemia genome
Open accessAbstract
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.
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Recurrent somatic point mutations in IDH1 and IDH2 are found in a wide variety of cancers, including glioblastoma multiforme and acute myeloid leukemia.
“Recurrent somatic point mutations in the genes coding for isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) are found in a wide variety of cancers, including glioblastoma multiforme (GBM) (Yan et al., 2009) and acute myeloid leukemia (AML) (Dang et al., 2016; Mardis et al., 2009).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Mardis et al., 2009
IDH1 mutations occur somatically in more than 70% of grade II-III gliomas and secondary glioblastomas, and in 8.5% of acute myeloid leukemias.
“Mutations in human cytosolic isocitrate dehydrogenase I (IDH1) occur somatically in >70% of grade II-III gliomas and secondary glioblastomas, and in 8.5% of acute myeloid leukemias (AML)”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Mardis et al., 2009
IDH1 R132 mutations were observed in 8.5% of AML patients studied, with a significantly higher percentage in the subset lacking cytogenetic abnormalities.
“These IDH1 R132 mutations were observed in 8.5% of AML patients studied, and a significantly higher percentage of mutation was observed in the subset of patients whose tumors lacked cytogenetic abnormalities”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Mardis et al., 2009
In an AML case with an IDH1 mutation sequenced in its entirety, there were a relatively small total number of somatic, non-synonymous mutations.
“In an AML case with an IDH1 mutation that was sequenced in its entirety (Mardis et al., 2009), there were a relatively small total number of somatic, non-synonymous mutations.”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Mardis et al., 2009
IDH1/2 mutations have been identified in a range of tumor types, including solid tumors such as gliomas and chondrosarcomas and blood cancers like acute myelogenous leukemia.
“IDH1/2 mutations have been identified in a range of tumor types, including solid tumors (e.g., gliomas and chondrosarcomas) and blood cancers like acute myelogenous leukemia (169, 170, 171).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [170]
There is a lack of evidence that 2HG acts as a mutagen.
“the lack of evidence that 2HG was acting as a mutagen (Mardis et al., 2009)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Mardis et al., 2009
Genomic sequencing of gliomas and acute myelogenous leukemia identified mutations in two isoforms of NADP+-dependent isocitrate dehydrogenase (IDH1 and IDH2).
“Genomic sequencing of gliomas (Parsons et al., 2008; Yan et al., 2009) and acute myelogenous leukemia (Mardis et al., 2009) identified mutations in two isoforms of NADP+-dependent isocitrate dehydrogenase (IDH1 and IDH2).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Mardis et al., 2009
D-2-HG accumulation under pathogenic conditions may contribute to tumorigenicity by stabilizing HIF-1α and impairing collagen biogenesis.
“the concentrations at which it accumulates under pathogenic conditions suggests HIF-1α stabilisation and impaired collagen biogenesis may contribute to tumorigenicity126-130.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [129]
Treatment of AML with targeted therapies is particularly promising due to the fact that AMLs have far fewer mutations than most other adult cancers, with an average of only 13 mutations.
“Treatment of AML with targeted therapies is particularly promising due to the fact that AMLs have far fewer mutations than most other adult cancers, with an average of only 13 mutations (Mardis et al, 2009; Cancer Genome Atlas Research Network, 2013).”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Mardis et al, 2009
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“(Marcucci et al., 2010; Mardis et al., 2009).”
BackgroundInteractions between epigenetics and metabolism in cancers
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- Authors
- Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., Fulton, L. A., Locke, D. P., Magrini, V. J., Abbott, R. M., Vickery, T. L., Reed, J. S., Robinson, J. S., Wylie, T., Smith, S. M., Carmichael, L., Eldred, J. M., Harris, C. C., Walker, J., Peck, J. B., Du, F., Dukes, A. F., Sanderson, G. E., Brummett, A. M., Clark, E., McMichael, J. F., Meyer, R. J., Schindler, J. K., Pohl, C. S., Wallis, J. W., Shi, X., Lin, L., Schmidt, H., Tang, Y., Haipek, C., Wiechert, M. E., Ivy, J. V., Kalicki, J., Elliott, G., Ries, R. E., Payton, J. E., Westervelt, P., Tomasson, M. H., Watson, M. A., Baty, J., Heath, S., Shannon, W. D., Nagarajan, R., Link, D. C., Walter, M. J., Graubert, T. A., DiPersio, J. F., Wilson, R. K., & Ley, T. J.
- Affiliations
- Washington University in St. Louis (US)
- Alvin J. Siteman Cancer Center (US)
- ORCID
- Mardis, Elaine R.
- Ding, Li
- Larson, David E.
- McLellan, Michael D.
- Chen, Ken
- Koboldt, Daniel C.
- Fulton, Robert S.
- McGrath, Sean D.
- Magrini, Vincent J.
- Vickery, Tammi L.
- Wylie, Todd
- Walker, Jason
- McMichael, Joshua F.
- Pohl, Craig S.
- Tang, Yuzhu
- Ries, Rhonda E.
- Payton, Jacqueline E.
- Tomasson, Michael H.
- Watson, Mark A.
- Heath, Sharon
- Link, Daniel C.
- Walter, Matthew J.
- Graubert, Timothy A.
- DiPersio, John F.
- Wilson, Richard K.
- Ley, Timothy J.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-09-10
- Volume
- 361
- Issue
- 11
- Pages
- 1058-1066
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3201812
- OpenAlex
- W2134061682
- Cited by
- 2,219
- References
- 30
- Citations by year
- 2026: 35 · 2025: 44 · 2024: 57 · 2023: 76 · 2022: 81 · 2021: 107 · 2020: 104 · 2019: 115 · 2018: 120 · 2017: 126 · 2016: 136 · 2015: 154 · 2014: 163 · 2013: 197 · 2012: 251
- FWCI
- 154.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (U54HG003079)
- National Cancer Institute (P01CA101937)
- National Center for Research Resources (UL1RR024992)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- acute myeloid leukemia, somatic mutations, IDH1 mutation, NPM1 mutation, NRAS mutation, cytogenetically normal AML, tumor genome sequencing
- MeSH terms
- Nucleophosmin, Adult, DNA Mutational Analysis, Female, Gene Frequency, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Leukemia, Myeloid, Acute, Genome, Human, Point Mutation, Sequence Analysis, DNA
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