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.
The pharmacogenomics journal. 2020 Oct 03 [Epub ahead of print]
Lars C Steggink, Hink Boer, Coby Meijer, Joop D Lefrandt, Leon W M M Terstappen, Rudolf S N Fehrmann, Jourik A Gietema
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands., Department of Internal Medicine, Division of Vascular Medicine, University Medical Center Groningen, University of Groningen, Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands., Medical Cell BioPhysics, University of Twente, Drienerlolaan 5, 7522 NB, Enschede, The Netherlands., Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. .