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

• Published in: The pharmacogenomics journal Vol. 21; no. 2; pp. 152 - 164
• Main Authors: Steggink, Lars C., Boer, Hink, Meijer, Coby, Lefrandt, Joop D., Terstappen, Leon W. M. M., Fehrmann, Rudolf S. N., Gietema, Jourik A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2021; Nature Publishing Group
• Subjects: 45/43; 692/308; 692/308/409; Adolescent; Adult; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - genetics; Chemotherapy; Cisplatin; Cohort Studies; Complications and side effects; Drug therapy; Endothelial cells; Endothelial Cells - drug effects; Gene Expression; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics - methods; Genotype; Human Genetics; Humans; Male; Middle Aged; Neoplasms, Germ Cell and Embryonal - drug therapy; Neoplasms, Germ Cell and Embryonal - genetics; Oncology; Oncology, Experimental; Organoplatinum Compounds - therapeutic use; Pharmacotherapy; Platinum; Polymorphism, Single Nucleotide - genetics; Psychopharmacology; Rac2 protein; Risk factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Testes; Testicular cancer; Testicular Neoplasms - drug therapy; Testicular Neoplasms - genetics; Young Adult; Germany
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/s41397-020-00191-8

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.