Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia The Cancer Genome Atlas Research Network

  • Voigt P
  • Reinberg D
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Abstract

BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear.

METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis.

RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories.

CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).

Author-supplied keywords

  • Acute
  • Acute: classification
  • Acute: genetics
  • Adult
  • CpG Islands
  • DNA
  • DNA Methylation
  • DNA: methods
  • Epigenomics
  • Female
  • Gene Expression
  • Gene Fusion
  • Genome, Human
  • Human
  • Humans
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid, Acute: classification
  • Leukemia, Myeloid, Acute: genetics
  • Male
  • MicroRNAs
  • MicroRNAs: genetics
  • Middle Aged
  • Mutation
  • Myeloid
  • Sequence Analysis, DNA
  • Sequence Analysis, DNA: methods

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Authors

  • Philipp Voigt

  • Danny Reinberg

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