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

Lars C Steggink, Hink Boer, Coby Meijer, Joop D Lefrandt, Leon W M M Terstappen, Rudolf S N Fehrmann, Jourik A Gietema*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Number of pages13
JournalPharmacogenomics journal
DOIs
Publication statusPublished - 3-Oct-2020

Keywords

  • LONG-TERM SURVIVORS
  • METABOLIC SYNDROME
  • CISPLATIN
  • EXPRESSION
  • NEPHROTOXICITY
  • ACTIVATION
  • BLEOMYCIN
  • APOPTOSIS
  • NECROSIS
  • INJURY

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