Mack Taralynn, Vlasschaert Caitlyn, von Beck Kelly, Silver Alexander J, Heimlich J Brett, Poisner Hannah, Condon Henry Robert, Ulloa Jessica, Sochacki Andrew L, Spaulding Travis P, Kishtagari Ashwin, Bejan Cosmin A, Xu Yaomin, Savona Michael R, Jones Angela, Bick Alexander
medRxiv. 2023 Nov 9:2023.11.08.23298270. doi: 10.1101/2023.11.08.23298270.
Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. Here, we present and validate a CHIP targeted sequencing assay that is affordable (∼$8/sample), accurate and highly scalable. To demonstrate the utility of this assay, we detected CHIP in a cohort of 456 individuals with DNA collected at multiple timepoints in the Vanderbilt BioVU biobank and quantified clonal expansion rates over time. A total of 101 individuals with CHIP were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction (VAF) at both timepoints. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. We further describe the mutation co-occurrence and clonal competition between multiple driver mutations.
不确定潜能的克隆性造血（CHIP）是一种常见的与年龄相关的现象，当造血干细胞在一组髓系肿瘤中常见的特定基因中获得突变，然后进行克隆性扩增时就会发生这种现象。目前用于检测CHIP的测序分析方法并未针对这些变异的检测进行优化，并且应用于大型队列或连续测序时成本过高。在此，我们展示并验证了一种针对CHIP的靶向测序分析方法，该方法价格实惠（约8美元/样本）、准确且具有高度可扩展性。为了证明该分析方法的实用性，我们在范德比尔特生物样本库中对456名个体的多个时间点采集的DNA进行检测，以确定CHIP，并随时间量化克隆扩增率。共鉴定出101名患有CHIP的个体，并使用两个时间点的变异等位基因频率（VAF）计算个体水平的克隆扩增率。观察到驱动基因的克隆扩增率存在差异，但个体水平也存在显著的异质性，这强调了克隆扩增的多因素性质。我们进一步描述了多个驱动突变之间的突变共现和克隆竞争。
