Gabriella Miller Kids First Pediatric Research Program in Germline and Somatic Variants in Myeloid Malignancies in Children

de novo Acute Myeloid Leukemia (AML) and Down Syndrome AML (DS-AML), to establish a database comprised of genomic and transcriptome information which can be interrogated for both somatic and germline variants. Identification of the somatic variants will provide valuable data on the potential genes and pathways that can be targeted for therapeutic purposes. In addition, interrogation of the host's constitutional genome may yield valuable information about potential germline variants that, in combination with the somatic data, might provide a more informed approach to patient care. For those patients with predisposition mutations, chemotherapy alone might not be adequate for cure, and stem cell transplantation might be required. Also, those who might be at high risk of adverse secondary events (cardiac complications, secondary malignancies, etc.) can be identified early and their therapy can be tailored to minimize anticipated complications. Thus, we propose that the optimum outcome can only be obtained through comprehensive interrogation of the somatic and germline genomes to fully annotate the genomic makeup of the leukemia and its host. Knowing the genomic and transcriptomic makeup of these patients, along with a full complement of clinical characteristics for this cohort, will be critical for making strong correlations which may aid in therapeutic development for future patients. The de novo AML, DS-AML, and Acute Promyelocytic Leukemia (APL) cases were all collected through clinical protocols conducted by the Children's Oncology Group (COG). In addition to funding from the Gabriella Miller Kids First Pediatric Research Program, the DS-AML cohort was specifically funded by the Lifespan to Understand Down syndrome (INCLUDE) Project.]]>
All samples utilized in this study were from participants in COG clinical trials. Patients enrolled on COG trial AAML1031, “A Phase III Randomized Trial for Patients with de novo AML using Bortezomib and Sorafenib for Patients with High Allelic Ratio Ratio FLT3/ITD”, represent the de novo AML cases. The Down Syndrome AML samples came from participants on COG trial AAML1531, “Risk Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome” and COG trial AAML08B1, “Biology Study of Transient Myeloproliferative Disorder (TMD) in Children with Down Syndrome". Inclusion from these studies as part of the Gabriella Miller project was based on available clinical covariates and availability of adequate specimens for testing.]]>
Advances in genome sequencing have allowed the identification of somatic variants as potential therapeutic targets. Although myeloid disorders in children may show morphologic similarities to that seen in adults, the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) AML initiative (Meshinchi, PI) clearly demonstrated that somatic genomic and transcriptome variants are highly distinct in children and young adults, and in fact there are variants that are uniquely restricted to younger children. TARGET AML initiative, although modest in number, helped to identify numerous somatic alterations with high therapeutic potential in younger AML patients. In addition to identification of somatic variants, analysis of the germline data provided a glimpse into the constitutional make-up of patients with AML. The identification of numerous “function altering” variants may provide an insight into possible interactions between the host and the disease, where these germline variants might alter AML risk (predisposition), response to therapy (altering target expression, drug metabolism), susceptibilities to short and long term complications, including infectious and cardiac complications, or modify risk of secondary malignancies. Armed with data from initial sequencing efforts in AML, we are poised to take full advantage of the available sequencing technology to conduct the most comprehensive genome and transcriptome interrogation of myeloid disorders in children in specimens we have amassed over the last decade. This study will build upon knowledge derived from TARGET AML and help to build a complete sequence database of childhood myeloid malignancies that will enable research to benefit future patients.]]>