Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Sci Rep. 2018 Jan 24;8(1):1508. doi: 10.1038/s41598-018-19590-w.

Abstract

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10-5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10-9, empirical P = 1.3 × 10-7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / metabolism*
  • Carboplatin / administration & dosage
  • Carboplatin / metabolism*
  • Carcinoma, Ovarian Epithelial / drug therapy*
  • Female
  • Genome, Human
  • Genome-Wide Association Study*
  • Humans
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics
  • Paclitaxel / administration & dosage
  • Paclitaxel / metabolism*
  • Polymorphism, Single Nucleotide

Substances

  • ABCC2 protein, human
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Carboplatin
  • Paclitaxel