慢性缺血性心力衰竭中的克隆性造血：DNMT3A 和 TET2 驱动基因突变的克隆大小对预后的作用。

Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations.

机构信息

Department of Medicine, Cardiology, Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

German Center for Cardiovascular Research DZHK, Berlin, Germany, partner site Frankfurt Rhine-Main, Germany.

出版信息

Eur Heart J. 2021 Jan 20;42(3):257-265. doi: 10.1093/eurheartj/ehaa845.

DOI:10.1093/eurheartj/ehaa845

PMID:33241418

Abstract

AIMS

Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF.

METHODS AND RESULTS

We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF < 0.5%), 29% with only one DNMT3A- or TET2-CH-driver mutations above the respective cut-off level and 42% in patients harbouring both DNMT3A- and TET2-CH-driver mutations above the respective cut-off levels. In carriers of a DNMT3A mutation with VAF ≥ 1.15%, 5-year mortality was 31%, compared with 18% mortality in those with VAF < 1.15% (P = 0.048). Likewise, in patients with TET2 mutations, 5-year mortality was 32% with VAF ≥ 0.73%, compared with 19% mortality with VAF < 0.73% (P = 0.029).

CONCLUSION

The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

摘要

目的

表观遗传调节因子 DNMT3A 和 TET2 的体细胞突变导致造血细胞的克隆扩增（克隆性造血；CH）与慢性缺血性心力衰竭（CHF）的预后不良相关。我们分析的目的是为 CHF 中 CH 的预后意义定义一个变异等位基因频率（VAF）的阈值。

方法和结果

通过纠错扩增子测序分析了 419 例 CHF 患者的骨髓和外周血衍生细胞。通过从截尾数据的时间依赖性接收者操作特征（ROC）曲线分析中最大化灵敏度加特异性来优化截断 VAF。56.2%的患者携带 DNMT3A-（N=173）或 TET2-（N=113）突变，VAF>0.5%，59 例患者同时携带这两种基因突变。生存 ROC 分析显示 TET2 突变的最佳截断值为 0.73%，DNMT3A 突变的截断值为 1.15%。在未检测到任何 DNMT3A 或 TET2 突变（VAF<0.5%）的患者中，5 年死亡率为 18%，只有一个 DNMT3A 或 TET2-CH 驱动突变超过各自的截断水平的患者中，5 年死亡率为 29%，同时携带 DNMT3A 和 TET2-CH 驱动突变超过各自截断水平的患者中，5 年死亡率为 42%。在 VAF≥1.15%的 DNMT3A 突变携带者中，5 年死亡率为 31%，而 VAF<1.15%的患者死亡率为 18%（P=0.048）。同样，在 TET2 突变患者中，VAF≥0.73%的患者 5 年死亡率为 32%，而 VAF<0.73%的患者死亡率为 19%（P=0.029）。