Treatment regimens for pediatric leukemia rely heavily on the use of the anthracyclines daunorubicin and doxorubicin. Pediatric cancer patients with Down syndrome (DS) constitute a population at particularly greater risk (3.4-fold relative risk) for anthracycline-related cardiotoxicity. The Children's Oncology Group has documented development of cardiomyopathy in 17.5% of children with DS treated for acute myeloid leukemia with an anthracycline-containing regimen. We hypothesize that preexistent alterations in mitochondrial DNA (mtDNA) in the hearts of individuals with DS contribute to enhance the cardiotoxicity of anthracyclines. The extent and type of mtDNA alterations in hearts from individuals with DS have not been investigated.
In specific aim 1, we will examine the presence and frequency of deletions in mtDNA in 11 heart samples from donors with DS and 22 samples from age-matched donors without DS. The presence and frequency of mtDNA deletions will be investigated with a sensitive """"""""single molecule"""""""" long distance polymerase chain reaction. Individual mtDNA deletion variants will be characterized by cloning and direct sequencing to identify the affected genes and to precisely map mtDNA breakpoints.
In aim 2, the presence of mtDNA mutations in heart samples from donors with DS will be documented by direct sequencing of the mitochondrial genomes with a state of the art parallel sequencing system at Ambry Genetics. The parallel sequencing system allows detection and characterization of mitochondrial genome-wide heteroplasmies at the >5% level. For comparison, the presence of mtDNA variants will be investigated in heart samples from age- and sex- matched donors without DS. Polymorphic mtDNA variants and mutations with pathogenic potential will be identified by detailed sequence annotations assisted by bioinformatics resources such as MITOMAP and PhyloTree. Completion of the proposed work will provide a novel catalogue on the extent of mtDNA abnormalities in hearts from individuals with DS. This work will provide a rational foundation for collaborative studies with investigators from the Children's Oncology Group to determine the extent to which specific alterations in mtDNA influence the risk of cardiotoxicity among survivors of pediatric cancers with DS.

Public Health Relevance

Pediatric cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. Two research aims will investigate the presence of genetic variants in cardiac mitochondrial DNA from donors with DS. The proposed work will provide the foundation for functional and clinical studies with investigators from the Children's Oncology Group directed towards the identification of risk factors for anthracycline-related cardiotoxicity in cancer patients with DS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1)
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Giacoia, George
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State University of New York at Buffalo
Schools of Pharmacy
United States
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Hefti, Erik; Bard, Jonathan; Blanco, Javier G (2017) Analysis of Heteroplasmic Variants in the Cardiac Mitochondrial Genome of Individuals with Down Syndrome. Hum Mutat 38:48-54
Hefti, Erik; Blanco, Javier G (2017) Pharmacotherapeutic Considerations for Individuals with Down Syndrome. Pharmacotherapy 37:214-220
Hoefer, Carrie C; Quiñones-Lombraña, Adolfo; Blair, Rachael Hageman et al. (2016) Role of DNA Methylation on the Expression of the Anthracycline Metabolizing Enzyme AKR7A2 in Human Heart. Cardiovasc Toxicol 16:182-92
Hefti, Erik; Blanco, Javier G (2016) Anthracycline-Related Cardiotoxicity in Patients with Acute Myeloid Leukemia and Down Syndrome: A Literature Review. Cardiovasc Toxicol 16:5-13
Hoefer, Carrie C; Blair, Rachael Hageman; Blanco, Javier G (2016) Development of a CART Model to Predict the Synthesis of Cardiotoxic Daunorubicinol in Heart Tissue Samples From Donors With and Without Down Syndrome. J Pharm Sci 105:2005-2008
Hefti, Erik; Blanco, Javier G (2016) Pharmacokinetics of Chemotherapeutic Drugs in Pediatric Patients With Down Syndrome and Leukemia. J Pediatr Hematol Oncol 38:283-7
Quiñones-Lombraña, Adolfo; Blanco, Javier G (2015) Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM). Biochim Biophys Acta 1852:1420-7