Chaix Marie-A, Parmar Neha, Kinnear Caroline, Lafreniere-Roula Myriam, Akinrinade Oyediran, Yao Roderick, Miron Anastasia, Lam Emily, Meng Guoliang, Christie Anne, Manickaraj Ashok Kumar, Marjerrison Stacey, Dillenburg Rejane, Bassal Mylène, Lougheed Jane, Zelcer Shayna, Rosenberg Herschel, Hodgson David, Sender Leonard, Kantor Paul, Manlhiot Cedric, Ellis James, Mertens Luc, Nathan Paul C, Mital Seema
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Adult Congenital Centre, Montréal Heart Institute, Université de Montréal, Montréal, Canada.
JACC CardioOncol. 2020 Dec 15;2(5):690-706. doi: 10.1016/j.jaccao.2020.11.004. eCollection 2020 Dec.
Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging.
This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors.
We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed.
Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (, ) provided protection from cardiotoxicity in cardiomyocytes.
Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778).
尽管存在已知的临床风险因素，但预测蒽环类药物心脏毒性仍然具有挑战性。
本研究旨在为儿童癌症幸存者的蒽环类药物心脏毒性建立一个临床和遗传风险预测模型。
我们对289名自接触蒽环类药物至少3年的儿童癌症幸存者进行了外显子组测序。在一项巢式病例对照设计中，选择183例尽管使用低剂量阿霉素（≤250mg/m²）但左心室射血分数降低的病例患者，以及106例尽管阿霉素剂量>250mg/m²但左心室射血分数保留的对照患者作为极端表型。对罕见/低频变异进行合并，以鉴定病例患者和对照患者之间变异差异富集的基因。在人诱导多能干细胞衍生的心肌细胞中评估了5个排名靠前的基因的表达水平，并在一个重复队列中证实了变异富集情况。使用随机森林开发了一个包含遗传和临床预测因素的风险预测模型。
病例患者和对照患者之间有31个基因的变异差异富集（p<0.001）。与89.6%的对照患者相比，只有42.6%的病例患者在这些基因中存在变异（优势比：0.09；95%置信区间：0.04至0.17；p=3.98×10⁻¹⁰）。与仅基于临床因素的模型相比，一个包含临床和遗传因素的心脏毒性风险预测模型具有更高的预测准确性和更低的错误分类率。体外抑制基因相关途径（如……）可保护心肌细胞免受心脏毒性。
我们的研究鉴定了心脏损伤途径基因中的变异，这些变异可预防心脏毒性，并为延迟性蒽环类药物心脏毒性预测模型的开发提供了依据，还为心脏保护药物的开发提供了自噬基因的新靶点。（预防儿童癌症幸存者的心脏后遗症[PCS2]；NCT01805778）
