Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse

Cancer Res. Volume 76, Issue 8 p.2197-2205, 3 March 2016 10.1158/0008-5472.CAN-15-1015

The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting.

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

• OCG TARGET Data Matrix (link is external) Office of Cancer Genomics
• 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.