Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have been rarely investigated. In this study, we developed and validated a CK-specific gene expression signature. Differential gene expression analysis between the CK and non-CK groups using data from 348 patients with AML and MDS-EB from four cohorts revealed enrichment of the downregulated genes localized on chromosome 5q or 7q, suggesting that haploinsufficiency due to the deletion of these chromosomes possibly underlies CK pathogenesis. We built a robust transcriptional model for CK prediction using LASSO regression for gene subset selection and validated it using the leave-one-out cross-validation method for fitting the logistic regression model. We established a 10-gene CK signature (CKS) predictive of CK with high predictive accuracy (accuracy 94.22%; AUC 0.977). CKS was significantly associated with shorter overall survival in three independent cohorts, and was comparable to that of previously established risk stratification models for AML. Furthermore, we explored of therapeutic targets among the genes comprising CKS and identified the dysregulated expression of superoxide dismutase 1 (SOD1) gene, which is potentially amenable to SOD1 inhibitors.
复杂核型（CK）与急性髓系白血病（AML）及伴原始细胞增多的骨髓增生异常综合征（MDS-EB）的不良预后相关。转录组学分析增进了我们对髓系肿瘤疾病机制及风险分层的理解，但针对CK的特异性基因表达特征研究尚少。本研究开发并验证了一种CK特异性基因表达特征。通过对来自四个队列的348例AML和MDS-EB患者数据，进行CK组与非CK组的差异基因表达分析，发现位于5q或7q染色体的下调基因显著富集，提示这些染色体缺失导致的单倍体不足可能是CK发病机制的基础。我们采用LASSO回归进行基因子集筛选，构建了稳健的CK预测转录模型，并通过留一交叉验证法对逻辑回归模型进行拟合验证。最终建立了一个包含10个基因的CK特征（CKS），其预测CK具有高准确性（准确率94.22%；AUC 0.977）。在三个独立队列中，CKS与较短的总生存期显著相关，其预测效能与既往建立的AML风险分层模型相当。此外，我们在构成CKS的基因中探索了潜在治疗靶点，发现超氧化物歧化酶1（SOD1）基因表达失调，该靶点可能适用于SOD1抑制剂治疗。
肿瘤(癌症)患者之家