Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy

Pharmacogenomics J. 2021 Apr;21(2):152-164. doi: 10.1038/s41397-020-00191-8. Epub 2020 Oct 3.


Genetic variation may mediate the increased risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients compared to the general population. Involved single nucleotide polymorphisms (SNPs) might differ from known CVD-associated SNPs in the general population. We performed an explorative genome-wide association study (GWAS) in TC patients. TC patients treated with platinum-based chemotherapy between 1977 and 2011, age ≤55 years at diagnosis, and ≥3 years relapse-free follow-up were genotyped. Association between SNPs and CVD occurrence during treatment or follow-up was analyzed. Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) provided insight into enriched gene sets, i.e., biological themes. During a median follow-up of 11 years (range 3-37), CVD occurred in 53 (14%) of 375 genotyped patients. Based on 179 SNPs associated at p ≤ 0.001, 141 independent genomic loci associated with CVD occurrence. Subsequent, DEPICT found ten biological themes, with the RAC2/RAC3 network (linked to endothelial activation) as the most prominent theme. Biology of this network was illustrated in a TC cohort (n = 60) by increased circulating endothelial cells during chemotherapy. In conclusion, the ten observed biological themes highlight possible pathways involved in CVD in chemotherapy-treated TC patients. Insight in the genetic susceptibility to CVD in TC patients can aid future intervention strategies.

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents / therapeutic use*
  • Cardiovascular Diseases / genetics*
  • Cohort Studies
  • Endothelial Cells / drug effects
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Genomics / methods
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neoplasms, Germ Cell and Embryonal / drug therapy*
  • Neoplasms, Germ Cell and Embryonal / genetics*
  • Organoplatinum Compounds / therapeutic use*
  • Polymorphism, Single Nucleotide / genetics
  • Testicular Neoplasms / drug therapy*
  • Testicular Neoplasms / genetics*
  • Young Adult


  • Antineoplastic Agents
  • Organoplatinum Compounds

Supplementary concepts

  • Testicular Germ Cell Tumor