Pharmacogenetic variants in the molecular characterization initiative: a report from the children's oncology group.
In 3,177 pediatric cancer patients enrolled in the COG Molecular Characterization Initiative, germline analysis of 13 pharmacogenes identified at least one CPIC-defined actionable pharmacogenomic phenotype in 93%, with similar overall prevalence across ancestry groups and allele frequencies closely matching external population cohorts.
Open original publication →What the AI sees
In 3,177 pediatric cancer patients enrolled in the COG Molecular Characterization Initiative, germline analysis of 13 pharmacogenes identified at least one CPIC-defined actionable pharmacogenomic phenotype in 93%, with similar overall prevalence across ancestry groups and allele frequencies closely matching external population cohorts.
Research significance
The study demonstrates a high prevalence of guideline-defined pharmacogenomic phenotypes; it is reasonable to hypothesize, but not shown here, that incorporating these results into pediatric oncology prescribing could improve drug selection or dosing and reduce toxicity.
Source abstract
BACKGROUND: The Childhood Cancer Data Initiative Molecular Characterization Initiative (MCI) provides molecular testing to patients with select tumors treated at Children's Oncology Group (COG) sites, advancing our understanding of the genetic basis of pediatric cancers and their treatment. However, the frequency of actionable pharmacogenomic variants in this cohort has not yet been explored. METHODS: Germline exome sequencing data were generated by the Institute for Genomic Medicine at Nationwide Children's Hospital. Clinically actionable pharmacogenetic variants for 13 genes were based on guidelines by the Clinical Pharmacogenetics Implementation Consortium. Pharmacogenomic diplotypes were extracted using PharmCAT. The T1K computational method was used to infer HLA alleles. Genetic ancestry was estimated by iAdmix using 1000 genomes as reference. Observed variant allele frequencies were compared to gnomAD and All of Us cohorts. RESULTS: Pharmacogenomic diplotypes were extracted for 3,177 patients. Most patients had a central nervous system (CNS) tumor (69%). Genetic composition of the population was diverse with 51% European, 21% Admixed American, and 9% African. Ninety-three percent (n = 2,940) of patients had at least one actionable pharmacogenomic phenotype necessitating modification to one or more medications. We did not observe a difference across ancestral populations in the frequency of individuals carrying at least one actionable variant (p = 0.07). Variant and allele frequencies were similar to those in the gnomAD and All of Us cohorts (R2>0.99). CONCLUSION: Overall, the vast majority (93%) of patients diagnosed with pediatric cancer within the MCI had an actionable pharmacogenomic phenotype for 13 pharmacogenes evaluated.