Neupane Achal, Petrykey Kateryna, Li Kendrick, French Jennifer, Zhou Xin, Wang Jian, Im Cindy, Dixon Stephanie B, Ehrhardt Matthew J, Mulrooney Daniel A, Jefferies John L, Gramatges M Monica, Chow Eric J, Bhatia Smita, Robison Leslie L, Ness Kirsten K, Hudson Melissa M, Burridge Paul W, Armstrong Gregory T, Yasui Yutaka, Sapkota Yadav
Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
JAMA Netw Open. 2025 Jun 2;8(6):e2515793. doi: 10.1001/jamanetworkopen.2025.15793.
Cancer therapy-related cardiomyopathy (CCM) is an important concern for childhood cancer survivors. In the general population, rare variants in TTN and BAG3 are associated with an increased risk of familial dilated cardiomyopathy, and common variants are associated with a decreased risk of sporadic dilated cardiomyopathy.
To examine associations of common and rare protein-altering variants (PAVs) in TTN and BAG3 with late-onset CCM risk in childhood cancer survivors.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study with a prospective follow-up included childhood cancer survivors from the St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS) with prior exposure to anthracyclines and/or chest-directed radiation. Cancer therapy-related cardiomyopathy was clinically assessed in SJLIFE and self-reported in CCSS, with severity graded using Common Terminology Criteria for Adverse Events, version 4.03. The data analysis was conducted from January 4, 2023, to March 6, 2025.
Late-onset CCM.
Multivariable logistic regression was used to evaluate the association of common variants in TTN and BAG3 with late-onset CCM risk, adjusting for relevant demographic and cancer treatment exposures. In SJLIFE alone, 7 echocardiographic parameters were assessed. Rare PAVs were examined using Fisher exact test. Cohort-specific results were combined using meta-analytic approaches.
The cohort included 1843 childhood cancer survivors from SJLIFE (median [IQR] age at CCM diagnosis, 34.9 [28.0-42.3] years; 53.2% male) and 4577 from CCSS (median [IQR] age at CCM diagnosis, 32.0 [23.0-41.0] years; 51.6% female). In the combined sample of European ancestry survivors from SJLIFE (205 with CCM grade ≥2) and CCSS (248 with CCM grade ≥2), common variants rs3829746-C in TTN (odds ratio, 0.81; 95% CI, 0.68-0.97) and rs2234962-C in BAG3 (odds ratio, 0.79; 95% CI, 0.65-0.95) were associated with a decreased risk of late-onset CCM. In SJLIFE African ancestry survivors, no association was observed with either of the common variants. Rare PAVs were not associated with late-onset CCM in European or African ancestry survivors. In European ancestry survivors, both rs3829746-C and rs2234962-C were also associated with reduced left ventricular end-systolic volume (β [SE], -1.90 [0.65] and -2.68 [0.64], respectively) and global longitudinal peak strain (β [SE], -0.31 [0.13] and -0.30 [0.12]) and with increased left ventricular ejection fraction (β [SE], 0.62 [0.27] and 0.86 [0.27], respectively).
The findings of this cohort study show that common variants in TTN and BAG3 are associated with a decreased risk of late-onset CCM among childhood cancer survivors, while rare PAVs showed no association.
癌症治疗相关的心肌病（CCM）是儿童癌症幸存者的一个重要问题。在一般人群中，TTN和BAG3基因的罕见变异与家族性扩张型心肌病风险增加相关，而常见变异与散发性扩张型心肌病风险降低相关。
研究TTN和BAG3基因中常见和罕见的蛋白质改变变异（PAVs）与儿童癌症幸存者迟发性CCM风险的关联。
设计、地点和参与者：这项回顾性队列研究并进行前瞻性随访，纳入了圣裘德终身队列（SJLIFE）和儿童癌症幸存者研究（CCSS）中的儿童癌症幸存者，这些幸存者既往接受过蒽环类药物和/或胸部定向放疗。SJLIFE对癌症治疗相关的心肌病进行了临床评估，CCSS则通过自我报告进行评估，使用不良事件通用术语标准4.03对严重程度进行分级。数据分析于2023年1月4日至2025年3月6日进行。
迟发性CCM。
采用多变量逻辑回归评估TTN和BAG3基因常见变异与迟发性CCM风险的关联，并对相关人口统计学和癌症治疗暴露因素进行调整。仅在SJLIFE中，评估了7项超声心动图参数。使用Fisher精确检验检查罕见的PAVs。采用荟萃分析方法合并队列特异性结果。
该队列包括1843名来自SJLIFE的儿童癌症幸存者（CCM诊断时的中位[四分位间距]年龄为34.9[28.0 - 42.3]岁；53.2%为男性）和4577名来自CCSS的儿童癌症幸存者（CCM诊断时的中位[四分位间距]年龄为32.0[23.0 - 41.0]岁；51.6%为女性）。在来自SJLIFE（205例CCM分级≥2）和CCSS（248例CCM分级≥2）的欧洲血统幸存者合并样本中，TTN基因中的常见变异rs3829746 - C（比值比，0.81；95%置信区间，0.68 - 0.97）和BAG3基因中的rs2234962 - C（比值比，0.79；95%置信区间，0.65 - 0.95）与迟发性CCM风险降低相关。在SJLIFE非洲血统幸存者中，未观察到与任何一种常见变异的关联。在欧洲或非洲血统幸存者中，罕见的PAVs与迟发性CCM无关。在欧洲血统幸存者中，rs3829746 - C和rs2234962 - C均还与左心室收缩末期容积降低（β[标准误]，分别为 - 1.90[0.65]和 - 2.68[0.64]）、整体纵向峰值应变降低（β[标准误]， - 0.31[0.13]和 - 0.30[0.12]）以及左心室射血分数增加（β[标准误]，分别为0.62[0.27]和0.86[0.27]）相关。
这项队列研究的结果表明，TTN和BAG3基因的常见变异与儿童癌症幸存者迟发性CCM风险降低相关，而罕见的PAVs未显示出关联。
