Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

NEJM. 368: p2059-2074. 30 May 2013 10.1056/NEJmoa1301689

Background: Many of the mutations that contribute to AML pathogenesis are still undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear.

Methods: We analyzed the genomes of 200 clinically-annotated cases of de novo acute myeloid leukemia occurring in adults, using whole genome sequencing (50 cases) or whole exome sequencing (150 cases), mRNA and miRNA sequencing, and DNA methylation analysis.

Results: AML genomes are minimally mutated compared to 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. 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples (99.5%) had at least one non-synonymous mutation in one of 9 categories of genes/events that are almost certainly relevant for pathogenesis, including transcription factor fusions (18% of cases), NPM1 (27%), tumor-suppressor genes (15.5%), DNA methylation-related genes (43.5%), signaling genes (59%), chromatin-modifying genes (30.5%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (13.5%).Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories.

Conclusions: Comprehensive genomic analyses have allowed us to identify at least one potential driver mutation in nearly all AML patients, and have revealed that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study will serve as a foundation for the understanding of AML pathogenesis, classification, and risk stratification.

Data in the GDC

• GDC Manifests
  • Open-Access Data - Download Manifest (39 Files)
  • Controlled-Access Data - Download Manifest (2 Files) | WGS Files (4 Files)

Supplemental Data

These data represent a data freeze from January 8, 2013.

The data are supported by different organizations. All data marked by [Supplementary] were created by the manuscript authors and you should contact the corresponding author for support.

Files larger than 1 MB have their actual size noted in parentheses. The text of the link in brackets indicates the file type/format; abbreviations: tsv, tab-separated values; txt, plain text file; tgz, compressed UNIX tape archive (tar) file (to unpack: tar -xzf filename.tgz)

• Complete LAML Sample List
  • Standardized freeze list [tsv]
  • Full Sample list [tsv]
  • LAML Sample Barcodes [txt]
  • BAM Freeze List (build36) [txt]
• Mutations
  • Level 2 MAF archives containing exome-based somatic mutations [tar.gz]
• RNA Expression
  • Data Matrix Files [Supplementary]:
    • RNAseq GAF 2.0 read count [txt.gz] (8.4 MB)
    • RNAseq GAF 2.0 normalized RPKM [txt.gz] (9.8 MB)
  • Level 3 Data Archives - IlluminaGA RNASeq [tgz] (1.1 GB)
  • Level 2 Data Archives - Affymetrix Human Genome U133 Plus 2.0 Array [tgz] (65 MB)
  • Level 1 Data Archives - Affymetrix Human Genome U133 Plus 2.0 Array [tgz] (787 MB)
• SNP and Copy Number
  • Level 3 Data Archives - Polymorphisms identified using the Affymetrix SNP 6 platform [tgz]
  • Level 2 Data Archives
    • Polymorphisms identified using the Affymetrix SNP 6 platform (20 GB)
    • Mutations identified using low-pass whole-genome sequencing the IlluminaGA platform [tgz]
  • Level 1 Data Archives - Polymorphisms identified using the Affymetrix SNP 6 platform (12 GB)
• miRNA
  • Data Matrix Files [Supplementary, miRBase v13]:
    • pre-miRNA seq (precursor):
      • read count [tgz]
      • RPM (normalized read counts per million) [txt.gz]
    • mature/star strand (MIMAT)
      • read count [tgz]
      • RPM (normalized read counts per million) [txt.gz]
  • Level 3 miRNA Sequence data [tgz] (7 MB)
• Methylation
  • Level 3 Data Archives - Level 3 DNA Methylation data [HM 27 tgz] (114 MB) [HM 450 tgz] (1.9 GB)
  • Level 2 Data Archives - Level 2 DNA Methylation data [HM 27 tgz] (80 MB) [HM 450 tgz] (1.8 GB)
  • Level 1 Data Archives - Level 1 DNA Methylation data [HM 27 tgz] (131 MB) [HM 450 tgz] (136 MB)
• Clinical
  • Patient Clinical Data: [tsv]
• Supplemental Data from NEJM paper [Supplementary]
  • Supplemental Table 01 [xlsx] (1.2 MB)
    • Per-sample table containing information on sex, race, cytogenetics, WBC, Fusions, SVs, risk groups, and a listing of all mutated genes across the cohort. Copy number amplifications are noted by a red background color, deletions are blue, and UPD events are green.
    • New version available: Updated Supplemental Table 01 [xlsx] (1.2 MB)
      Patient survival info brought up to date. The above version was used for all analysis in the manuscript, this update can be used for future studies.
  • Supplemental Table 04 [xls|tsv] - Summary of assays performed for each sample
  • Supplemental Table 05 [xls|tsv] - Segments of copy number amplification and deletion
  • Supplemental Table 06 [xls|tsv] (13 MB|4.2 MB) - All somatic mutations with annotation and read counts from DNA and RNA sequencing
  • Supplemental Table 11 [xls|HTML] (1.2 MB)
    • Germline truncational variants in all 200 cases. Sample identifiers have been removed to anonymize the data
    • Supplemental Table 11 (all genes) [tsv]
    • Supplemental Table 11 (AML genes) [tsv]
    • Supplemental Table 11 (COSMIC genes) [tsv]
  • Supplemental Table 13 [xls|tsv] - Gene Fusions
  • Supplemental Table [xls] - This spreadsheet gives the unsupervised NMF consensus clustering results for mRNAseq (n=179) and miRNAseq (n=187) from Figs. 4A,B of the TCGA NEJM publication.

Additional Resources

• GDC Encyclopedia
• Descriptions of TCGA data are provided in the TCGA Barcode Encyclopedia Page
• Genomic Data Commons Portal