已知儿童癌症幸存者对蒽环类药物引起的心脏功能障碍具有遗传易感性，但这一点在青少年和年轻成人 (AYA) 患者中尚未得到充分证明。我们的目的是确定之前发现的与儿童癌症患者心脏功能障碍相关的变异是否对 AYA 癌症患者有类似的影响。在先前用蒽环类药物治疗的 253 个 AYA 中选择了 45 个变体进行分析。我们确定了与心脏功能障碍相关的四种变异：SLC10A2:rs7319981 (p = 0.017)、SLC22A17:rs4982753 (p = 0.019)、HAS3:rs2232228 (p = 0.023)和RARG:rs2229774 (p = 0.050）。 HAS3:rs2232228 和 SLC10A2:rs7319981 在我们的 AYA 癌症幸存者群体中显示出显着的影响，其方向与儿童癌症幸存者中报告的方向相反。进一步分析了宿主基因的遗传变异与 AYA 癌症幸存者心脏毒性的其他关联。然后在一组诱导多能干细胞衍生的心肌细胞中评估宿主基因，以评估用阿霉素处理时表达水平的变化。观察到 HAS3 和 SLC22A17 表达显着上调 (p<0.05)，而 RARG 观察到不显着的蒽环类药物反应。我们的研究表明，遗传对 AYA 癌症患者的心脏功能障碍有影响，但儿童和 AYA 癌症幸存者之间的遗传作用可能存在差异。© 2024。作者，获得 Springer Nature 独家许可有限的。

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.