一个新的 6p21.2 基因座与癌症治疗诱导的儿童癌症幸存者心脏功能障碍有关。
A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors.
机构信息
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
出版信息
J Natl Cancer Inst. 2022 Aug 8;114(8):1109-1116. doi: 10.1093/jnci/djac115.
BACKGROUND
Adult survivors of childhood cancer are at increased risk of cardiac late effects.
METHODS
Using whole-genome sequencing data from 1870 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). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. 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 or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). 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 1651 SJLIFE survivors of European ancestry showed statistically 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 2 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.
背景
儿童癌症幸存者患心脏晚期并发症的风险增加。
方法
利用来自圣裘德终身队列（SJLIFE）研究的 1870 名欧洲裔幸存者的全基因组测序数据，研究人员检查了与射血分数（EF）和临床评估的癌症治疗引起的心脏功能障碍（CCD）相关的遗传变异。在 SJLIFE 中的 301 名非洲裔幸存者和儿童癌症幸存者研究中的 4020 名欧洲裔幸存者中验证了具有统计学意义的发现。所有统计检验均为双侧检验。
结果
在 SJLIFE 中的欧洲裔幸存者中，位于 KCNK17 附近的一个变体与 EF（rs2815063-A：EF 降低 1.6%；P=2.1×10-8）表现出全基因组显著关联，该关联在 SJLIFE 中的非洲裔幸存者中得到了复制（EF 降低 1.5%；P=0.004）。rs2815063-A 还显示出严重或致残或危及生命的 CCD 的风险增加 1.80 倍（P=0.008），并在 4020 名欧洲裔儿童癌症幸存者研究幸存者中得到了复制（优势比=1.40；P=0.04）。值得注意的是，rs2815063-A 仅在暴露于多柔比星的幸存者中与 EF（EF 降低 3.3%）和 CCD（2.97 倍）的相关性更强。在 1651 名欧洲裔 SJLIFE 幸存者的全血 DNA 甲基化数据中，rs2815063-A 与 KCNK17 增强子的失调具有统计学显著相关性（假发现率<5%），在 263 名非洲裔幸存者中得到了复制。同样，根据 75 名幸存者的 RNA 测序，rs2815063-A 与 KCNK17 的下调相关。
结论
利用北美最大的 2 个儿童癌症幸存者队列和特定于幸存者的多基因组功能数据，我们确定了一个新的 CCD 风险位点，该位点与多柔比星诱导的心脏功能障碍具有特异性，并强调 KCNK17 的失调是这种遗传关联的潜在分子机制。
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