MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

J Clin Oncol. Volume 35, Issue 35 p.3964-3977, 25 October 2017 10.1200/JCO.2017.74.7451

Purpose

Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction.

Patients and Methods

To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing.

Results

By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells.

Conclusion

To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

This study characterized TARGET cases as described below:

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

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   • GDC DTT ( Download, User's Guide)
   • GDC API ( User’s Guide)

Controlled Access Data

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2. Download a token from the GDC Data Portal
   • GDC Data Portal ( Launch, User’s Guide)
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   • GDC API ( User’s Guide)

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