Descriptive "pharmacogenomics analysis" of the CBTN PBTA cohort

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Outcomes in pediatric cancer have steadily improved over the last several decades. As a direct result, there is increased focus on decreasing the long-term side effects of treatment. One emerging field to address this issue is “Pharmacogenomics”, using genotype to predict an individual’s response to specific medications in order to identify patients at increased risk for treatment related toxicities. Specifically, single nucleotide polymorphisms can be used to predict toxicities to known drugs. To date, there has been little focus on this in the pediatric cancer population aside from thiopurine methyltransferase (TPMT) activity, used to evaluate mercaptopurine metabolism. Patients who are TPMT homozygous deficient will have increased myelosuppression related to the drug. More recently, genetic polymorphisms have been identified that are associated with increased toxicity of other chemotherapy agents and supportive care medications (such as opiods) but have not yet been used to guide clinical decision making. And, no specific intervention has been identified to prevent or improve the side effects.

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What are the goals of this project?

To better understand the prevalence of specific genotypes that might impact toxicities to treatment, we propose a bioinformatic analysis of the 900+ constitutional genomes sequenced as part of the Pediatric Brain Tumor Atlas in order to describe the prevalence of specific genotypes reported in the literature.

What is the impact of this project?

An example of the potential impact of the genotype-phenotype relationship in pediatric cancers is vincristine, a vinca alkaloid that inhibits microtuble formation. Vincristine is a chemotherapy agent that is repeatedly administered in many different brain tumor protocols, including low-grade gliomas and medulloblastoma, and is associated with significant peripheral neuropathies often requiring dose reductions. Two different studies have identified a single nucleotide polymorphism (SNP) in the promoter of the CEP72 gene, rs924607, in both adult and pediatric patients with acute lymphoblastic leukemia to be associated with increased rates of grades 2-4 vincristine associated peripheral neuropathy1,2. The role of this SNP has not been evaluated in other cancers, such as low-grade gliomas, medulloblastoma, and rhabdomyosarcoma, despite the wide use of vincristine in these treatment regimens. This study will help to define the frequency of a known risk-allele for vincristine-related neuropathy in pediatric oncology patients with a spectrum of diagnoses. It will also aim to validate an intervention to help prevent reductions in therapy due to toxicity.

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