Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals
Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals
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DOI：
10.1182/blood.2019004362
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发表时间：
2020-04-02
期刊：
影响因子：
20.3
通讯作者：
Huls, Gerwin
中科院分区：
文献类型：
--
作者：
van Zeventer, Isabelle A.;de Graaf, Aniek O.;Huls, Gerwin
贫血是造血衰老的一个主要且目前人们知之甚少的临床表现。随着年龄的增长，携带获得性白血病相关突变的造血克隆会扩增并变得可检测到，现在称为克隆造血（CH）。为了研究 CH 与老年人贫血之间的关系，我们探讨了老年贫血患者 CH 的情况和动态。我们从基于人群的前瞻性生命线队列 (n = 167 729) 中，根据世界卫生组织标准 (n = 676) 选择了所有 60 岁以上患有贫血的个体，并选择了 1:1 匹配的对照参与者。对 1298 名个体的外周血中 27 个驱动基因中变异等位基因频率 (VAF) 为 1% 或更高的获得性突变进行了分析。为了跟踪克隆随时间的演变，我们纳入了所有可用的后续样本 (n = 943)。与对照个体 (39.1%；P = .007) 相比，贫血个体 (46.6%) 更容易检测到 CH。尽管与对照个体相比，贫血个体中常见检测到的 DTA 突变（DNMT3A、TET2、ASXL1）没有观察到差异，但贫血人群中其他突变也有所丰富，包括 TP53 和 SF381。与营养缺乏的个体不同 (P = .84)，患有慢性炎症性贫血和不明原因贫血的个体与匹配的对照个体相比，CH 患病率更高（分别为 P = .035 和 P = .017）。后续分析显示，克隆可能会扩大和下降，通常在 44 个月内仅显示 VAF 略有增加（平均 0.56%），无论是否存在贫血。特定的突变与不同的生长速度和获得额外打击的倾向相关。与较小的克隆相比（
Anemia is a major and currently poorly understood clinical manifestation of hematopoietic aging. Upon aging, hematopoietic clones harboring acquired leukemia-associated mutations expand and become detectable, now referred to as clonal hematopoiesis (CH). To investigate the relationship between CH and anemia of the elderly, we explored the landscape and dynamics of CH in older individuals with anemia. From the prospective, population-based Lifelines cohort (n = 167 729), we selected all individuals at least 60 years old who have anemia according to World Health Organization criteria (n = 676) and 1:1 matched control participants. Peripheral blood of 1298 individuals was analyzed for acquired mutations at a variant allele frequency (VAF) of 1% or higher in 27 driver genes. To track clonal evolution over time, we included all available follow-up samples (n = 943). CH was more frequently detected in individuals with anemia (46.6%) compared with control individuals (39.1%; P = .007). Although no differences were observed regarding commonly detected DTA mutations (DNMT3A, TET2, ASXL1) in individuals with anemia compared with control individuals, other mutations were enriched in the anemia cohort, including TP53 and SF381. Unlike individuals with nutrient deficiency (P = .84), individuals with anemia of chronic inflammation and unexplained anemia revealed a higher prevalence of CH (P = .035 and P = .017, respectively) compared with their matched control individuals. Follow-up analyses revealed that clones may expand and decline, generally showing only a subtle increase in VAF (mean, 0.56%) over the course of 44 months, irrespective of the presence of anemia. Specific mutations were associated with different growth rates and propensities to acquire an additional hit. In contrast to smaller clones (