PRAGYA SANTRA, AMITY UNIVERSITY KOLKATA
Genetic variation is promoting the risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients due to alterations of SNPs (Single Nucleotide Polymorphism) from normal sequences. TC patients treated with platinum-based chemotherapy (PBC) when genotyped, were analyzed with 141 independent genomic loci, containing 324 SNPs contributing to CVD occurrence. Studies revealed patients attributed to bleomycin, etoposide, and cisplatin chemotherapy are prone to the coronary artery and atherosclerotic disease. Isolating germline DNA and SNP array was performed for genotyping analysis.
SNPs in glutathione-S-transferase genes GSTP1 and GSTM3 resulted in neurotoxicity and ototoxicity in platinum-treated TC patients. 5-α-reductase type-II (SRD5A2) genes associated with SNPs caused the metabolic syndrome. A recent study in 188 platinum-treated TC patients reported an SNP in the solute carrier gene, SLC16A5, resulting in cisplatin-induced ototoxicity. SNP in the Wolframin ER transmembrane glycoprotein (WFS1) leads to ototoxicity in TC survivors. All these focus on genetic variation and biological pathways to analyze the risk for CVD in TC patients treated with PBC.
Input data analyzed for Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) framework, examined genes in loci comparing them to share gene set memberships to predict similar functions directing autosomal loci not overlapping with the MHC region, resulted in 187 genes mapped to 129 loci. Gene set enrichment analysis was conducted to understand the biology between SNPs and CVD occurrence, reporting 33 gene sets. Most enriched gene sets were the RAC2/RAC3 sub-networks, linking to chemotherapy toxicity, resulting in endothelial activation, by oxidized low-density lipoprotein in the human umbilical vein and dysfunction where several circulating endothelial cells were measured in 60 patients. Further analysis resulted in ten biological themes highlighting the pathways involved in the occurrence of CVD in chemotherapy-treated TC patients which includes the RAC2/RAC3 network, metabolism and adiposity, immune response, and caspase-cascade/apoptosis.
Additionally, RAC2 leads to neovascularization and leukocyte adhesion to the endothelial cell. According to the atherosclerosis model, Rac2 suppressed macrophage IL-1β expression preventing plaque calcification. Contrarily, decreased RAC2 expression, and increased IL-1β resulted in calcifying coronary arteries. SNPs in RAC2 lead to cardiotoxicity due to anthracycline chemotherapy. RAC3 inhibits senescence and induces inflammatory response after TNF stimulation. Moreover, Rac3 modifies the induction of endothelial dysfunction.
Concluding, the RAC2/RAC3 network plays a role in atherosclerosis and senescence leading to the progression of CVD in TC patients. SNP analysis in CVD and TC patients’ population-wise focuses on the differences of SNPs. Concentrating on genetic variants is now a promising approach for future studies on genetic susceptibility considering relevant biomarkers in CVD in TC patients.
SOURCES:
- Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy; Lars C. Steggink, et al, 03 October 2020; The Pharmacogenomics Journal; DOI: https://doi.org/10.1038/s41397-020-00191-8
- Vascular damage in testicular cancer patients: A study on endothelial activation by bleomycin and cisplatin in vitro; Janine Nuver et al; January 1, 2010; Oncology Reports; Volume 23; Issue 1; Pages: 247-253; DOI: https://doi.org/10.3892/or_00000630
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