Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
Cancer Cell. 2023 Jun 12;41(6):1017-1031.e4. doi: 10.1016/j.ccell.2023.04.006. Epub 2023 May 4.
Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2, spliceosome, or TP53 mutations and absent for DNMT3A, and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of "CHIP" and "CCUS."
关于可能驱动恶性进展的克隆性造血演变的知识对于临床决策至关重要。我们通过对前瞻性基于人群的 Lifelines 队列中 3359 名个体的 7045 个连续样本进行纠错测序，研究了克隆进化的格局，特别关注了细胞增多症和细胞减少症。剪接体（SRSF2/U2AF1/SF3B1）和 JAK2 突变克隆在中位数为 3.6 年的时间内显示出最高的增长率，而 DNMT3A 和 TP53 的克隆大小仅略有增加，与细胞增多症或细胞减少症无关。然而，同一突变的个体之间存在很大差异，表明存在非突变相关因素的调节。克隆扩增不依赖于经典的癌症风险因素（例如，吸烟）。JAK2、剪接体或 TP53 突变发生骨髓恶性肿瘤诊断的风险最高，而 DNMT3A 不存在这种风险，而且大多数情况下都伴有细胞增多症或细胞减少症。这些结果为指导“CHIP”和“CCUS”监测的高危进化模式提供了重要的见解。
