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.
Pharmacogenomics J. 2021 Apr;21(2):152-164. doi: 10.1038/s41397-020-00191-8. Epub 2020 Oct 3.
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.
遗传变异可能介导了化疗治疗的睾丸癌（TC）患者与普通人群相比心血管疾病（CVD）风险增加。涉及的单核苷酸多态性（SNP）可能与普通人群中已知的与 CVD 相关的 SNP 不同。我们在 TC 患者中进行了一项探索性全基因组关联研究（GWAS）。TC 患者于 1977 年至 2011 年间接受铂类化疗治疗，诊断时年龄≤55 岁，且无病生存期≥3 年，进行基因分型。分析 SNP 与治疗或随访期间 CVD 发生之间的关联。数据驱动的复杂性状表达优先整合（DEPICT）提供了对富集基因集的深入了解，即生物学主题。在中位随访 11 年（范围 3-37 年）期间，在 375 名接受基因分型的患者中，有 53 名（14%）发生了 CVD。基于与 p≤0.001 相关的 179 个 SNP，确定了 141 个与 CVD 发生相关的独立基因组位点。随后，DEPICT 发现了十个生物学主题，其中 RAC2/RAC3 网络（与内皮细胞激活有关）是最突出的主题。通过在 TC 队列（n=60）中化疗期间循环内皮细胞的增加，说明了该网络的生物学特性。总之，观察到的十个生物学主题突出了化疗治疗的 TC 患者中与 CVD 相关的可能途径。对 TC 患者 CVD 遗传易感性的了解可以辅助未来的干预策略。
