BACKGROUND Cisplatin-based chemotherapy (CBCT) is part of standard treatment of several cancers. In testicular cancer (TC) survivors, an increased risk of developing metabolic syndrome (MetS) is observed. In this epigenome-wide association study, we investigated if CBCT relates to epigenetic changes (DNA methylation) and if epigenetic changes render individuals susceptible for developing MetS later in life. We analyzed methylation profiles, using the MethylationEPIC BeadChip, in samples collected ~ 16 years after treatment from 279 Norwegian TC survivors with known MetS status. Among the CBCT treated (n = 176) and non-treated (n = 103), 61 and 34 developed MetS, respectively. We used two linear regression models to identify if (i) CBCT results in epigenetic changes and (ii) epigenetic changes play a role in development of MetS. Then we investigated if these changes in (i) and (ii) links to genes, functional networks, and pathways related to MetS symptoms. RESULTS We identified 35 sites that were differentially methylated when comparing CBCT treated and untreated TC survivors. The PTK6-RAS-MAPk pathway was significantly enriched with these sites and infers a gene network of 13 genes with CACNA1D (involved in insulin release) as a network hub. We found nominal MetS-associations and a functional gene network with ABCG1 and NCF2 as network hubs. CONCLUSION Our results suggest that CBCT has long-term effects on the epigenome. We could not directly link the CBCT effects to the risk of developing MetS. Nevertheless, since we identified differential methylation occurring in genes associated with conditions pertaining to MetS, we hypothesize that epigenomic changes may also play a role in the development of MetS in TC survivors. Further studies are needed to validate this hypothesis.

中文翻译：

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顺铂治疗睾丸癌患者会导致表观基因组的长期变化。

背景技术基于顺铂的化学疗法（CBCT）是几种癌症的标准治疗的一部分。在睾丸癌（TC）幸存者中，观察到发生代谢综合征（MetS）的风险增加。在这项表观基因组范围的关联研究中，我们研究了CBCT是否与表观遗传学变化（DNA甲基化）有关，以及表观遗传学变化是否使个体易于在以后的生活中发展MetS。我们使用MethylationEPIC BeadChip分析了从279个具有已知MetS状况的挪威TC幸存者进行治疗后约16年收集的样品中的甲基化谱图。在经过治疗的CBCT（n = 176）和未经治疗的CBCT（n = 103）中，分别有61和34种MetS发生。我们使用两个线性回归模型来确定（i）CBCT是否导致表观遗传变化，以及（ii）表观遗传变化是否在MetS的发展中起作用。然后，我们调查（i）和（ii）中的这些变化是否与基因，功能网络和与MetS症状相关的途径相关。结果当比较CBCT治疗和未治疗的TC幸存者时，我们确定了35个甲基化差异的位点。PTK6-RAS-MAPk途径显着富集了这些位点，并以CACNA1D（涉及胰岛素释放）为网络中心推断了13个基因的基因网络。我们发现了名义的MetS关联和一个以ABCG1和NCF2为网络中心的功能基因网络。结论我们的结果表明CBCT对表观基因组具有长期影响。我们不能将CBCT的影响与发展MetS的风险直接联系起来。不过，由于我们确定了与MetS相关疾病相关基因中发生的甲基化差异，我们假设表观基因组的改变也可能在TC幸存者中MetS的发展中起作用。需要进一步的研究来验证这一假设。