The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

Nature Medicine. Volume 24, Issue 1 p.103-112, 11 December 2017 10.1038/nm.4439

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

This study characterized TARGET cases as described below:

GE = gene expression; CN = copy number, WGS = whole genome sequencing, WXS = Whole Exome Sequencing, TCS = targeted capture sequencing

In order to access Controlled TARGET AML data using the links below, users must submit an application for Authorized Access via dbGaP as described on dbGaP’s TARGET Study Page. To begin the application process, please view the information and instructions provided on the dbGaP Authorized Access Login Page under “dbGaP Data Download”.

Supplemental Data

• GDC Manifests
  • Controlled-Access Data Download Manifest (8 Files)
  • Open-Access Data Download Manifest (25 Files)
  • WGS CGI Files Download Manifest (209 Files)
• Copy Number Array
  • TARGET AML Copy Number Array Level 1 Data (Controlled)
  • TARGET AML Copy Number Array Level 2 Data (Controlled)
  • TARGET AML Copy Number Array Level 3 Data
  • TARGET AML Copy Number Array Data Metadata
• Gene Expression Array
  • TARGET AML Gene Expression Array Level 1 Data
  • TARGET AML Gene Expression Array Level 2 Data
  • TARGET AML Gene Expression Array Level 3 Data
  • TARGET AML Gene Expression Array Metadata
• mRNA-Seq
  • TARGET AML RNA-Seq Level 3 Data
  • TARGET AML RNA-Seq Level 3 Data (Controlled)
  • TARGET AML RNA-Seq Metadata
• miRNA-Seq
  • TARGET AML miRNA-Seq Level 3 Data
  • TARGET AML miRNA-Seq Level 4 Data
  • TARGET AML miRNA-Seq Metadata
• WXS
  • TARGET AML WXS Level 3 Data
  • TARGET AML WXS Level 3 Data (Controlled)
  • TARGET AML WXS Design
  • TARGET AML WXS Metadata
• Methylation Array
  • TARGET AML Methylation Array Level 1 Data (Controlled)
  • TARGET AML Methylation Array Level 2 Data
  • TARGET AML Methylation Array Level 3 Data
  • TARGET AML Methylation Array Level 4 Data
  • TARGET AML Methylation Array Metadata
• WGS
  • TARGET AML WGS Level 3 Data
  • TARGET AML WGS Level 3 Data (Controlled)
  • TARGET AML WGS Level 4 Data
  • TARGET AML WGS Metadata
• Targeted Capture Sequencing
  • TARGET AML Targeted Capture Sequencing Level 3 Data (Controlled)
  • TARGET AML Targeted Capture Sequencing Design
  • TARGET AML Targeted Capture Sequencing Metadata
• Miscellaneous Files
  • TARGET AML Sample Matrices
  • TARGET AML CGI Requested Reports (Controlled)

Additional Resources

• SRA - SRP012000 (link is external) NCBI

Instructions for Data Download

Open Access Data

1. Download the appropriate manifest file from the publication page
2. Use the manifest file to download data using the GDC Data Transfer Tool (DTT) or the GDC API
   • GDC DTT ( Download, User's Guide)
   • GDC API ( User’s Guide)

Controlled Access Data

1. Download the appropriate manifest file from the publication page
2. Download a token from the GDC Data Portal
   • GDC Data Portal ( Launch, User’s Guide)
3. Use the manifest file and token to download data using the GDC DTT or the GDC API
   • GDC DTT ( Download, User’s Guide)
   • GDC API ( User’s Guide)

For assistance, please contact the GDC Help Desk: support@nci-gdc.datacommons.io.