Abstract：
BACKGROUND: Splicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real-life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia-related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML.
METHODS: A total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML-related genes by next-generation sequencing.
RESULTS: We showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild-type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status.
CONCLUSIONS: In conclusions, we linked both pathogenic and VUS variants in AML-related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results.
METHODS: A total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML-related genes by next-generation sequencing.
RESULTS: We showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild-type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status.
CONCLUSIONS: In conclusions, we linked both pathogenic and VUS variants in AML-related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results.
摘要：
背景：拼接修改，基因组不稳定性，和低甲基化是促进骨髓增生异常和急性髓细胞性白血病（AML）的主要机制。在这项现实生活中的回顾性研究中，阐明血液恶性肿瘤中克隆造血的病理生理学，我们调查了在MDS和AML患者队列中,已知有致病意义的白血病相关基因突变和不确定临床意义的变异体(VUS)的临床意义.
方法：共有59名连续被诊断为MDS的受试者，48与AML，17例克隆性血细胞减少症患者通过下一代测序筛选AML相关基因的体细胞突变。
结果：我们显示TET2，SETBP1，ASXL1，EZH2，RUNX1，SRSF2，DNMT3A，和IDH1/2通常突变。MDS患者也表现出很高的遗传复杂性，特别是SETBP1。此外，SETBP1野生型或两种或两种以上同时发生的VUS变异的存在确定了一个预后较好的AML和MDS患者亚组,虽然单一SETBP1VUS变异的存在与预后较差有关，无论TET2突变状态。
结论：结论：我们将AML相关基因中的致病性和VUS变异与克隆造血联系起来；因此，我们建议将这些变异体作为白血病和骨髓增生异常的预后标志物.然而,我们需要在更大的前瞻性队列中进行进一步的研究来验证我们的结果.
方法：共有59名连续被诊断为MDS的受试者，48与AML，17例克隆性血细胞减少症患者通过下一代测序筛选AML相关基因的体细胞突变。
结果：我们显示TET2，SETBP1，ASXL1，EZH2，RUNX1，SRSF2，DNMT3A，和IDH1/2通常突变。MDS患者也表现出很高的遗传复杂性，特别是SETBP1。此外，SETBP1野生型或两种或两种以上同时发生的VUS变异的存在确定了一个预后较好的AML和MDS患者亚组,虽然单一SETBP1VUS变异的存在与预后较差有关，无论TET2突变状态。
结论：结论：我们将AML相关基因中的致病性和VUS变异与克隆造血联系起来；因此，我们建议将这些变异体作为白血病和骨髓增生异常的预后标志物.然而,我们需要在更大的前瞻性队列中进行进一步的研究来验证我们的结果.
