Outcome Definition Influences the Relationship Between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients

Genes (Basel). 2019 May 10;10(5):364. doi: 10.3390/genes10050364.

Abstract

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009-2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI:0.08-0.70; p= 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI:1.96-9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI:1.69-15.16; p= 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.

Keywords: cisplatin; genetic polymorphisms; kidney injury; nephrotoxicity; pharmacogenetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / genetics
  • Adult
  • Biomarkers, Pharmacological
  • Cisplatin / adverse effects*
  • Creatinine / blood
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics*
  • Endonucleases / metabolism
  • Gene Frequency
  • Glomerular Filtration Rate / drug effects
  • Humans
  • Kidney / drug effects
  • Kidney / pathology
  • Male
  • Middle Aged
  • Neoplasms, Germ Cell and Embryonal / drug therapy
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / metabolism
  • Organic Cation Transporter 2 / genetics*
  • Organic Cation Transporter 2 / metabolism
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Retrospective Studies
  • Testicular Neoplasms / drug therapy*
  • Testicular Neoplasms / genetics*
  • Testicular Neoplasms / metabolism
  • Xeroderma Pigmentosum Group D Protein / genetics*
  • Xeroderma Pigmentosum Group D Protein / metabolism

Substances

  • Biomarkers, Pharmacological
  • DNA-Binding Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • Creatinine
  • ERCC1 protein, human
  • Endonucleases
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human
  • Cisplatin

Supplementary concepts

  • Testicular Germ Cell Tumor