Longitudinal profiling of clonal hematopoiesis provides insight into clonal dynamics.
Longitudinal profiling of clonal hematopoiesis provides insight into clonal dynamics.
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DOI：
10.1186/s12979-022-00278-9
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发表时间：
2022-05-24
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不确定潜能克隆造血（CHIP），即突变造血干细胞与年龄相关的扩增，会带来多种衰老疾病的风险，包括血液癌症和心血管疾病。全外显子组或基因组测序可以检测 CHIP，但由于这些检测的成本较高，大多数群体研究都是横断面的，仅对每个个体的单个时间点进行测序。我们开发并验证了一种经济有效的单分子分子倒置探针测序 (smMIPS) 检测方法，用于检测 CHIP，针对 CHIP 中 11 个最常突变的基因以及 4 个复发突变热点。我们对从女性健康倡议队列的 182 名参与者收集的 548 个多时间点样本进行了测序，中位跨度为 16 年。我们检测到 178 个驱动突变在至少一个时间点内达到变异等位基因频率 ≥ 2%，其中许多在早期时间点可检测到远低于此阈值。大多数克隆突变（52.1%）随着时间的推移而扩展（中位倍增期为 7.43 年），而其他突变在没有任何细胞毒性治疗的情况下保持不变或大小减小。靶向 smMIPS 测序可以灵敏地测量 CHIP 中的克隆动态。达到CHIP常规阈值（2%频率）的突变往往会继续增长，表明CHIP获得后，一般不会丢失。具有成本效益的纵向分析 CHIP 的能力将使未来的研究能够调查为什么一些 CHIP 克隆会扩展，以及它们的动态与生物库规模的健康结果有何关系。在线版本包含可在 10.1186/s12979-022-00278-9 获取的补充材料。
Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays’ high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual. We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women’s Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale. The online version contains supplementary material available at 10.1186/s12979-022-00278-9.