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

Steggink, L. C., Boer, H., Meijer, C., Lefrandt, J. D., Terstappen, L. W. M. M., Fehrmann, R. S. N. & Gietema, J. A., 3-Oct-2020, In : Pharmacogenomics journal. 13 p.

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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
Publication statusPublished - 3-Oct-2020

    Keywords

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

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