Abstract 5583: Integrative genomic analyses on pediatric acute myeloid leukemia
Authors: Wai Daniel H. , Ries Rhonda E. , Considine Michael , Lee David W. , Liu Sun-Mei , O'Connor Nicole M. , Pepper Oliver , Bista Ranjan , Aleem Eiman , Azorsa David O. , Davidsen Tanja M. , Farley Toni , Guidry-Auvil Jaime , Farrar Jason E. , Smith Malcolm A. , Gerhard Daniela S. , Ochs MIchael F. , Mousses Spyro , Meshinchi Soheil , Arceci Robert J. 
Published: May 2015

Background

Acute myeloid leukemia (AML) is a complex and heterogeneous disease leading to a wide range of response variability to conventional therapy, excessive treatment related toxicity, and an overall poor outcome. The NCI supported Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative provided initial support for large-scale genomics to identify novel disease-associated genomic and epigenomic alterations that could be used to develop novel, targeted therapies for pediatric AML.

Patients

Diagnostic (Dx), remission (Rm), and relapse (Rel) samples were obtained from over 200 children with AML treated on the most recent Children's Oncology Group clinical trials. Data analyses were performed using Partek Genomics Suite 6.6 and Ingenuity Pathway Analysis.

Results

Methylation profiling (Illumina HumanMethylation27) identified 603 CpG sites significantly differentially methylated between Dx and Rm. In addition, 514 CpG sites were significantly differentially methylated between matched Rel and Rm (p&lt;0.05 FDR, change in β≥0.25). Pathway analysis using genes associated with these CpG sites identified significant (p&lt;0.01) over-representation of the WNT/β-catenin signaling pathway in Dx vs. Rm and in Rel vs. Rm.

Gene expression profiling (Affymetrix Human Gene 1.1 ST) revealed 1,142 significantly differentially expressed between Dx and normal bone marrow obatined from the blood bank. Similarly, there were 1,242 significantly differentially expressed genes between Rel and normal bone marrow (p&lt;0.05 FDR, fold-change≥2.00). Many expression differences were coordinated with methylation changes. Pathway analysis revealed 100 significantly (p&lt;0.05) over-represented pathways in Dx vs. normal, Rel vs. normal, or both.

Copy-number data analysis (Affymetrix Genome-Wide Human SNP 6.0) identified 180,379 significantly different regions in 254 Dx vs matched Rm. Similarly, 4,707 regions a significantly different in 49 Rel vs matched Rm (p&lt;0.01). Many regions were distinct to either Dx or Rel groups.

Whole-genome sequencing (Complete Genomics, Inc) was performed on 100 cases with matched Dx and Rm pairs and on 86 cases with matched Dx, Rel, and Rm samples. The frequencies of either somatic or germline variants were not significantly different when comparing Dx vs. Rel samples. Pathway analysis compared 1,528 mutated genes in the pediatric (TARGET) cohort with 1,963 mutated genes in adult de novo AML (TCGA cohort). Of the 85 and 80 significantly (p&lt;0.05) over-represented canonical pathways, respectively, there are 44 pathways in common and many could be targeted by existing drugs.

Conclusion

A combination of genomic approaches have identified genes and pathways that appear deregulated in pediatric AML. Many changes are specific to Dx or Rel sample groups, or to pediatric vs. adult AML. Further study into these genes and pathways may reveal candidate targets for therapeutic intervention.

Citation Format: Daniel H. Wai, Rhonda E. Ries, Michael Considine, David W. Lee, Sun-Mei Liu, Nicole M. O'Connor, Oliver Pepper, Ranjan Bista, Eiman Aleem, David O. Azorsa, Tanja M. Davidsen, Toni Farley, Jaime Guidry-Auvil, Jason E. Farrar, Malcolm A. Smith, Daniela S. Gerhard, MIchael F. Ochs, Spyro Mousses, Soheil Meshinchi, Robert J. Arceci. Integrative genomic analyses on pediatric acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5583. doi:10.1158/1538-7445.AM2014-5583