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Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children

Henk Visscher1, Colin J D Ross, S Rod Rassekh

  • 1University of British Columbia, Vancouver, British Columbia.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|September 9, 2011
PubMed
Abstract

Insights

Genetic variants in SLC28A3 and other genes are linked to anthracycline-induced cardiotoxicity (ACT) in children. Genetic risk profiling may help identify high-risk patients for safer treatment options.

Area of Science:

  • Genetics
  • Pharmacogenomics
  • Pediatric Oncology

Background:

  • Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction that limits the use of anthracyclines, a class of chemotherapy drugs.
  • ACT contributes significantly to morbidity and mortality in patients, particularly those treated for childhood cancers.

Purpose of the Study:

  • To identify genetic variants associated with the development of ACT in children undergoing anthracycline treatment.
  • To explore the potential of genetic risk profiling for personalized treatment strategies.

Main Methods:

  • A genome-wide association study (GWAS) was conducted, analyzing 2,977 single-nucleotide polymorphisms (SNPs) in 220 drug biotransformation genes.
  • A discovery cohort of 156 children was used, with subsequent replication in two independent cohorts totaling 284 patients.
  • A prediction model was developed combining identified genetic variants with clinical risk factors.

Main Results:

  • A significant association was found between the synonymous coding variant rs7853758 (L461L) in the SLC28A3 gene and ACT (OR, 0.35; P = 1.8 × 10(-5)).
  • Additional risk and protective variants were identified in genes including SLC28A1 and ATP-binding cassette transporters (ABCB1, ABCB4, ABCC1).
  • The prediction model accurately classified patients into risk groups: 75% of high-risk patients were predicted to develop ACT, while 96% of low-risk patients were predicted not to develop ACT.

Conclusions:

  • Multiple genetic variants in SLC28A3 and other genes are associated with ACT in pediatric cancer patients.
  • Genetic risk profiling, combined with clinical factors, can identify individuals at high risk for ACT.
  • This approach may enable the selection of safer treatment alternatives for high-risk pediatric patients, mitigating cardiotoxicity.

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