Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92–88.41, P < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06–55.35, P < 0.001). Currently, the ‘zygosity’ of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include ‘zygosity’ status of CHIP mutations and that future prognostication systems should take mutation ‘zygosity’ into account.
克隆造血可由单基因突变（如JAK2点突变引起CHIP）或嵌合染色体改变（如9号染色体杂合性缺失）导致。克隆造血与血液系统恶性肿瘤风险显著增加相关，但其按年化计算的转化绝对发生率较低。临床实践亟需改进转化风险的预后判断方法。我们假设，CHIP与mCA在同一基因位点共存（例如通过9号染色体伴随性杂合性缺失，将杂合性JAK2 CHIP突变为纯合性突变）可能对恶性转化风险具有重要预后意义。我们利用英国生物银行发现队列（n=451,180）验证该假设，并在BioVU队列（n=91,335）中进行验证。研究发现同时存在体细胞突变与mCA的个体罹患血液系统恶性肿瘤的风险显著增加（例如在BioVU队列中，JAK2 V617F与9号染色体拷贝中性杂合性缺失共存者的血液恶性肿瘤发生率更高；与单独存在JAK2 V617F相比：HR=54.76，95% CI=33.92–88.41，P<0.001；与单独存在9p CN-LOH相比：HR=44.05，95% CI=35.06–55.35，P<0.001）。目前临床检测中尚未常规报告CHIP突变的"接合性"状态，也未将其纳入CHIP转化风险的预后评估。基于这些发现，我们建议临床报告应包含CHIP突变的"接合性"状态，且未来的预后评估体系应考虑突变"接合性"因素。
Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk
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