Background Adult survivors of childhood cancer are at increased risk of cardiac late effects. Methods Using whole-genome sequencing data from 1,870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Significant findings were validated in 301 SJLIFE survivors of African ancestry and 4,020 survivors of European ancestry from the Childhood Cancer Survivor Study (CCSS). All statistical tests were 2-sided. Results A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10–8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction: 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe/disabling or life-threatening CCD and replicated in 4,020 CCSS survivors of European ancestry (OR = 1.40; P = .039). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1,651 SJLIFE survivors of European ancestry showed significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA-sequencing of 75 survivors. Conclusions Leveraging the two largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.

中文翻译：

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6p21.2 上的一个新基因座用于儿童癌症幸存者中癌症治疗引起的心功能障碍

背景 儿童癌症成年幸存者发生心脏迟发效应的风险增加。方法 在 St. Jude Lifetime Cohort (SJLIFE) 研究中，使用来自 1,870 名欧洲血统幸存者的全基因组测序数据，检查遗传变异与射血分数 (EF) 和临床评估的癌症治疗引起的心功能障碍 (CCD) 的关联。重要发现在来自儿童癌症幸存者研究 (CCSS) 的 301 名非洲血统 SJLIFE 幸存者和 4,020 名欧洲血统幸存者中得到验证。所有统计测试都是双侧的。结果 KCNK17 附近的一个变体在欧洲血统的 SJLIFE 幸存者中显示与 EF 的全基因组显着关联（rs2815063-A：EF 减少 = 1.6%；P = 2.1 × 10–8），这在非洲血统的 SJLIFE 幸存者中复制（EF 减少: 1.5%；P = .004)。rs2815063-A 还显示出 1.80 倍 (P = .008) 的严重/致残或危及生命的 CCD 风险，并在 4,020 名欧洲血统的 CCSS 幸存者中得到复制 (OR = 1.40; P = .039)。值得注意的是，rs2815063-A 在仅暴露于多柔比星的幸存者中特别相关，对 EF（EF 减少 3.3%）和 CCD（2.97 倍）有更强的影响。1,651 名欧洲血统 SJLIFE 幸存者的全血 DNA 甲基化数据显示 rs2815063-A 与 KCNK17 增强子失调（错误发现率 <5%）显着相关，这在 263 名非洲血统幸存者中得到复制。一致地，根据 75 名幸存者的 RNA 测序，rs2815063-A 与 KCNK17 下调相关。结论 利用北美最大的两个儿童癌症幸存者队列和幸存者特异性多基因组功能数据，