Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.

克隆性造血 (CH) 是由驱动血细胞克隆性扩增的体细胞基因组改变引起的。在健康个体的造血细胞中检测到的与血液系统恶性肿瘤相关的体细胞基因突变，称为不确定潜能的 CH(CHIP)，与髓系恶性肿瘤有关，而嵌合染色体改变 (mCA) 与淋巴恶性肿瘤有关。在这里，我们分析了英国生物库和麻省总医院布莱根生物库中 55,383 名个体的 CHIP 和 420,969 名无血液系统恶性肿瘤病史的常染色体 mCA。我们区分了骨髓和淋巴体细胞基因突变，以及骨髓和淋巴 mCA，发现两者都与谱系特异性血液系统恶性肿瘤的风险相关。更远，我们对外周血细胞计数参数的体细胞改变进行了综合分析，以分层发生髓系和淋巴系恶性肿瘤的风险。这些基因改变可以很容易地在临床测序面板中检测到，并与血细胞计数参数一起使用，以识别具有发生血液系统恶性肿瘤高风险的个体。