Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.
据报道，在包括急性髓系白血病（AML）在内的多种癌症中，黏连蛋白复合体的功能扰动会导致染色质结构和复制发生后续变化。其STAG2亚基的突变可能预示不良风险，这一点已获2022年欧洲白血病网指南认可，但现有证据受限于小样本量、临床结果的不一致观察以及其他黏连蛋白复合体亚基信息的缺乏。我们回顾性分析了来自多中心队列的1615例接受强化治疗的AML患者数据，发现STAG2突变具有独特的共突变模式，这些模式与正常核型（NK）以及IDH2、RUNX1、BCOR、ASXL1和SRSF2的并发突变相关。而RAD21突变则与正常核型（NK）及EZH2、KRAS、CBL和NPM1突变相关。携带STAG2突变的患者年龄较大，且白细胞、骨髓及外周血原始细胞计数较低。总体而言，无论是STAG2、RAD21、SMC1A还是SMC3突变，均未对完全缓解、无事件生存、无复发生存或总生存等临床结局表现出任何显著的独立影响。然而，我们发现各个黏连蛋白亚基的遗传改变几乎完全互斥。这种互斥性可能为通过合成致死策略治疗黏连蛋白突变AML提供理论基础。
肿瘤(癌症)患者之家