Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
Wellcome-Medical Research Council (MRC) Cambridge Stem Cell Institute, Cambridge, United Kingdom.
Blood. 2020 Jan 23;135(4):269-273. doi: 10.1182/blood.2019001807.
Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.
尽管随着年龄的增长，1 个或多个造血干细胞获得白血病相关的体细胞突变是不可避免的，但其后果差异很大，从临床上无明显表现的克隆性造血（CH）到白血病进展都有。为了研究遗传因素对 CH 的影响，我们对 52 对同卵（MZ）和 27 对异卵（DZ）双胞胎（年龄 70-99 岁）的血液 DNA 进行了深度靶向测序。使用这种高灵敏度的方法，我们在 62%的个体中发现了 CH（变异等位基因频率≥0.5%）。我们没有观察到 MZ 双胞胎内的 CH 一致性高于 DZ 双胞胎内的一致性，也没有观察到与偶然情况相符的一致性。然而，我们确实发现了 2 对 MZ 双胞胎，它们的两个双胞胎都携带有相同的罕见体细胞突变，表明存在共同的起源细胞。最后，在 3 对携带相同驱动基因突变的 MZ 双胞胎中，相隔 4 到 5 年采集的连续血液样本显示出克隆轨迹的双胞胎间存在很大的可变性。我们的研究结果表明，遗传基因组对成人 CH 的行为没有明显的影响，并提供了证据表明 CH 突变可能是在子宫内获得的。
