Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, and identified subunit-specific clinical, prognostic, and genetic characteristics suggestive of distinct ontogenies. We found that STAG2 mutations are acquired at MDS stage and are associated with secondary AML, adverse prognosis, and co-occurrence of secondary AML-type mutations. In contrast, mutations in RAD21, SMC1A and SMC3 share features with de novo AML with better prognosis, and co-occurrence with de novo AML-type lesions. The findings show the heterogeneous nature of cohesin complex mutations, and inform clinical and prognostic classification, as well as distinct biology of the cohesin complex.

粘连蛋白复合物成分（ STAG2、RAD21、SMC1A、SMC3和PDS5B）中的突变是骨髓增生异常肿瘤 (MDS) 和急性髓系白血病 (AML) 中反复出现的遗传驱动因素。不同的粘连蛋白亚基突变是否具有共同的临床特征和预后意义尚不清楚。我们分析了来自 Dana-Farber 癌症研究所 (DFCI) 和慕尼黑白血病实验室 (MLL) 的 790 名粘连蛋白突变患者，其中 390 名患者有可用的结果数据，并确定了提示不同个体发育的亚单位特异性临床、预后和遗传特征。我们发现STAG2突变是在 MDS 阶段获得的，并且与继发性 AML、不良预后以及继发性 AML 型突变的共存相关。相比之下， RAD21、SMC1A和SMC3的突变与新发 AML 具有相同的特征，具有更好的预后，并且与新发 AML 型病变同时发生。这些发现显示了粘连蛋白复合物突变的异质性，并为临床和预后分类以及粘连蛋白复合物的独特生物学提供了信息。