Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 35, Issue 35, Pages 3964-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1200/JCO.2017.74.7451
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Funding
- National Institutes of Health, National Cancer Institute [HHSN261200800001E]
- Children's Oncology Group Statistics and Data Center [U10CA180899, U10CA098413]
- National Clinical Trials Network Operations Center [U10CA180886]
- BC Cancer Foundation
- St Baldrick's Foundation Consortium
- Canadian Institutes of Health Research
- University of British Columbia
- Genome Canada
- Genome British Columbia
- Cancer Research Society
- Leukemia and Lymphoma Society of Canada
- Canadian Institutes of Health Research [FDN-143288]
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PurposeChildren 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 MethodsTo 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 samples1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples127 primary and 37 relapse sampleswere analyzed by using RNA sequencing.ResultsBy 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.ConclusionTo 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.
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