Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
Nat Commun. 2023 Sep 8;14(1):5536. doi: 10.1038/s41467-023-41315-5.
Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.
克隆性造血 (CH)-与突变造血克隆相关的年龄相关扩展-可以通过 CH 类型（例如，驱动基因 (CHIP) 的突变、染色体片段的获得/缺失和拷贝中性缺失 (mCAs) 以及性染色体的丢失）在频率和细胞适应性方面有所不同。共存的 CH 引发了关于它们的起源、选择和影响的问题。我们整合了多达 482,378 名英国生物库参与者的序列和基因芯片数据，以证明 CH 类型之间存在共享的遗传结构。我们的分析表明，不同类型的 CH 之间存在细胞进化权衡，在携带已建立的 CHIP 基因突变的个体中，LOY 的发生率较低。我们观察到 CHIP 和 mCAs 的共存，并在 TET2、DNMT3A 和 JAK2 处重叠，其中 CHIP 先于 mCA 获得。此外，携带重叠 CH 的个体未来患淋巴和髓系恶性肿瘤的风险很高。最后，我们利用 CH 特征的共享遗传结构来确定 15 个与白血病风险相关的新位点。
