Hematology and Transplant Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy.
Department of Medicine, Surgery, and Dentistry, University of Salerno, Baronissi, Italy.
Eur J Haematol. 2023 Nov;111(5):729-741. doi: 10.1111/ejh.14069. Epub 2023 Jul 27.
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.
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.
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.
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.
剪接修饰、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系白血病（AML）的核心机制。在这项真实的回顾性研究中，为了阐明血液恶性肿瘤中克隆性造血的病理生理学，我们研究了已知发病机制的白血病相关基因中的突变以及不确定临床意义的变异（VUS）在一组 MDS 和 AML 患者中的临床意义。
对 59 例连续诊断为 MDS、48 例 AML 和 17 例克隆性血细胞减少伴不明意义的患者进行了下一代测序的 AML 相关基因体细胞突变筛查。
我们表明 TET2、SETBP1、ASXL1、EZH2、RUNX1、SRSF2、DNMT3A 和 IDH1/2 是常见突变。MDS 患者也表现出较高的遗传复杂性，尤其是 SETBP1。此外，SETBP1 野生型或同时存在两种或更多种 VUS 变体的存在确定了 AML 和 MDS 患者预后较好的亚组，而单个 SETBP1 VUS 变体的存在与较差的预后相关，而与 TET2 突变状态无关。
总之，我们将 AML 相关基因中的致病性和 VUS 变体与克隆性造血联系起来；因此，我们建议将这些变体视为白血病和骨髓增生异常的预后标志物。然而，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。
