Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
Blood Adv. 2023 Oct 24;7(20):6092-6107. doi: 10.1182/bloodadvances.2023010045.
Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.
携带与遗传性血液恶性肿瘤（HHM）相关的种系变异的个体，其白血病发生风险具有高度可变性。我们对 HHM 前恶性状态的理解存在差距，这阻碍了设计有效的临床监测计划、提供个性化的预防性治疗以及为患者提供适当咨询的努力。我们使用了已知最大的国际比较性种系 RUNX1、GATA2 或 DDX41 变体携带者队列，这些携带者没有和有血液恶性肿瘤（HM），以确定在白血病发生前后，每种 HHM 综合征特有的遗传驱动因素模式。这些模式包括在早期发生的克隆性造血（CH）率方面存在显著异质性，RUNX1 和 GATA2 变体携带者在没有恶性肿瘤的情况下（无 HM 携带者）CH 的患病率很高。我们在无 HM 携带者中观察到 CH 的发生率较低。在无 HM 携带 RUNX1 且有 CH 的 RUNX1 携带者中，我们检测到 TET2、PHF6 和最常见的 BCOR 中的变体。这些基因在 RUNX1 驱动的恶性肿瘤中经常发生突变，这表明 CH 是 RUNX1 驱动的 HHM 恶性肿瘤的直接前体。RUNX1 和 DDX41 携带者的白血病发生通常分别由 RUNX1 和 DDX41 的第二次打击驱动。这项研究可能为开发 HHM 特异性临床试验和基因特异性临床监测方法提供信息。例如，现在可能有利于研究监测无 HM 携带 DDX41 的个体中 DDX41 低频二次打击的潜在益处。同样，有必要监测无 HM 携带 RUNX1 种系变体的个体，以获得 BCOR、PHF6 和 TET2 的体细胞变体以及 RUNX1 的第二次打击。
