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

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.

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

“…[157][158][159] In addition, the other male specific associations were in ATP10B and ARMC4 genes, which are cilia-related genes implicated in ocular, vascular, and neoplastic traits. 81,139,[160][161][162][163][164] Primary cilia cells are crucial in normal function of the smooth All rights reserved. No reuse allowed without permission.…”

“…[157][158][159] In addition, the other male specific associations were in ATP10B and ARMC4 genes, which are cilia-related genes implicated in ocular, vascular, and neoplastic traits. 81,139,[160][161][162][163][164] Primary cilia cells are crucial in normal function of the smooth muscles and play important roles in cell proliferation mechanisms. 165 In fact, primary cilia, through their dysfunction, contribute to cancer via interference in cancer signaling pathways, such as the Wnt signaling pathway.…”

Cisplatin for cancer therapy and overcoming chemoresistance

“…A genome-wide-association study (GWAS) was performed on single nucleotide polymorphisms (SNP) related to cardiovascular disease (CVD) in TC survivors treated with platinum-based medications, being less than 55 years old at diagnosis and having greater than 3 years of refraction-free survival. They identified 179 SNPs related to CVD; having prominent gene activity associated with the Rac/Rho family small GTPase-2/3 (RAC2/RAC3) network, adiposity, metabolic and immune deficiencies, and apoptosis [ 107 ]. RAC2/RAC3 pathways involve leukocyte adhesion to endothelial cells, endothelial activation, neovascularisation, and prevention of calcified plaque formation in arthrosclerosis [ 107 ].…”

“…They identified 179 SNPs related to CVD; having prominent gene activity associated with the Rac/Rho family small GTPase-2/3 (RAC2/RAC3) network, adiposity, metabolic and immune deficiencies, and apoptosis [ 107 ]. RAC2/RAC3 pathways involve leukocyte adhesion to endothelial cells, endothelial activation, neovascularisation, and prevention of calcified plaque formation in arthrosclerosis [ 107 ]. A higher risk of venous thromboembolism and bleeding in cisplatin-treated metastatic TC patients exist, particularly in patients having enlarged retroperitoneal lymph nodes [ 108 ].…”

Cardiovascular Safety Assessment in Cancer Drug Development

“…In that regard, preclinical studies have significantly improved the understanding of the genetic basis of cardiotoxicity. For example, genome‐wide association studies have identified numerous cardiotoxicity loci associated with anticancer drugs (ie, rs28714259 with doxorubicin, CBR3 and ABCB1 with trastuzumab), 25 , 26 , 27 and hiPSC models have shed further light regarding plausible genomic biomarkers that predict cardiotoxicity. 28 This knowledge that there exists a rare population that is genetically predisposed to cardiotoxicity has an impact on safety assessment during drug development and indicates that clinical trials may need to be much larger.…”