Boen Hanne M, Alaerts Maaike, Goovaerts Inge, Saenen Johan B, Franssen Constantijn, Vorlat Anne, Vermeulen Tom, Heidbuchel Hein, Van Laer Lut, Loeys Bart, Van Craenenbroeck Emeline M
Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium.
Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium.
Cardiooncology. 2024 Apr 30;10(1):26. doi: 10.1186/s40959-024-00231-3.
Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking.
We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111).
Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals.
In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.
在癌症治疗相关心脏功能障碍（CTRCD）患者中已鉴定出心肌病基因变异，提示CTRCD发生存在遗传易感性。与心肌病患者队列相比，CTRCD人群中基因检测的诊断率尚不清楚，且缺乏关于该人群应评估哪些基因的信息。
我们回顾性纳入了46例有蒽环类药物诱导的CTRCD病史的癌症患者（定义为左心室射血分数（LVEF）降至<50%且经超声心动图检查较基线降低≥10%）。对59个已确定的心肌病基因进行了基因检测。仅纳入意义不明确的变异和（可能）致病性变异。将基因检测的诊断率与匹配的扩张型心肌病（DCM，n = 46）患者队列和匹配的无心脏病患者队列（n = 111）进行比较。
CTRCD诊断时的平均LVEF为30.1±11.0%。患者诊断时年龄为52.9±14.6岁，30例（65.2%）为女性。大多数患者接受乳腺癌或淋巴瘤治疗，多柔比星等效剂量中位数为300mg/m²[112.5 - 540.0]。在29/46（63.0%）的CTRCD患者中鉴定出一种基因变异，其为致病性、可能致病性或意义不明确的变异，这与DCM队列相似（34/46，73.9%，p = 0.262），但显著高于阴性对照队列（47/111，39.6%，p = 0.018）。TTN变异在CTRCD队列中最为常见（占所有变异的43%）。CTRCD队列中鉴定出的所有（可能）致病性变异均为TTN中的截短变异。携带变异个体与未携带变异个体在CTRCD严重程度和恢复率方面无显著差异。
在这项病例对照研究中，有蒽环类药物诱导的CTRCD的癌症患者心肌病基因变异负担增加，与DCM队列相似。如果在更大规模的前瞻性研究中得到验证，将基因数据整合到CTRCD风险预测模型中可能会指导癌症治疗。此外，基因检测结果对患者在精准医疗方面以及对将接受遗传咨询的家庭成员都具有重要的临床意义。
