Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

不确定潜能的克隆性造血 (CHIP) 在 60 岁以后的患病率迅速增加，并且与恶性肿瘤、心脏病和缺血性中风的风险增加有关。CHIP 是由造血干细胞和祖细胞 (HSPC) 中的体细胞突变驱动的。由于 HSPC 中的突变通常会导致白血病，我们假设 HSPC 适应性在很大程度上有助于从 CHIP 向白血病的转变。HSPC 适应性被定义为相对于不携带或仅携带中性突变的细胞的增殖优势。如果不同基因的突变导致明显的适应性优势，则可以对患者进行分层。我们使用纵向测序量化了 12 岁以上突变对老年人的适应性影响，并开发了一种过滤方法，该方法考虑了个体突变背景以及突变共现，以量化个体变异的增长潜力。我们发现基因特异性适应性差异可以超过个体间差异，因此可以构成个性化临床管理的基础。