文章：

慢性淋巴细胞白血病患者中SPEN基因突变的突变谱及其临床影响

Mutational Landscape and Clinical Impact of SPEN Mutations in Patients with Chronic Lymphocytic Leukemia

原文发布日期：6 November 2025

DOI: 10.3390/cancers17213586

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:NOTCH1is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition toNOTCH1, mutations in the NOTCH1 regulatory pathway includingSPENhave been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis. Results:SPENmutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were missense. Compared withSPENwild type CLL patients,SPENmutated patients had a statistically higher frequency of IGHV unmutated status (79.5% vs. 57.8%,p= 0.004), CD38 positivity (73.3% vs. 52.4%,p= 0.01), ZAP70 positivity (77.3% vs. 58.3%,p= 0.01) and trisomy 12 (43.5% vs. 13.7%,p< 0.001). The most common gene mutations co-occurring withSPENmutations were as follows:NOTCH1(43.7%),TP53(22.9%),BIRC3(12.5%),SF3B1(10.4%),XPO1(8.3%),MUC2(6.2%),ATM(4.2%),FBXW7(4.2%), andBTK(4.2%). Patients withSPENmutated CLL had a significantly shorter time-to-first treatment compared to CLL patients with wild typeSPEN(2.5 vs. 4.07 years,p= 0.01). The finding of shorter time-to-first treatment inSPENmutated CLL patients was not maintained in a multivariable analysis. IGHV unmutated status,TP53disruption, and trisomy 12 remained independently predictive of a shorter time-to-first treatment in a multivariable analysis. Conclusions: These data show thatSPENmutations in CLL are associated with adverse prognostic impact and should be included in sequencing assays performed for the prognostic workup of CLL patients.

摘要翻译： 

背景/目的：NOTCH1基因在慢性淋巴细胞白血病（CLL）中频繁发生突变，是预后不良的标志物。除NOTCH1外，包括SPEN在内的NOTCH1调控通路突变在少数CLL病例中已有报道，且研究表明这些突变同样与患者不良预后相关。方法：本研究通过靶向测序和29基因组合检测对1617例CLL病例进行分析，并将结果与预后指标进行关联性研究。结果：在48例（2.9%）CLL患者中检测到SPEN突变：其中92.4%为有害突变（移码或无义截短突变），其余7.6%为错义突变。与SPEN野生型CLL患者相比，SPEN突变患者具有显著更高的IGHV未突变率（79.5% vs. 57.8%，p=0.004）、CD38阳性率（73.3% vs. 52.4%，p=0.01）、ZAP70阳性率（77.3% vs. 58.3%，p=0.01）及12号染色体三体发生率（43.5% vs. 13.7%，p<0.001）。与SPEN突变共现的最常见基因突变包括：NOTCH1（43.7%）、TP53（22.9%）、BIRC3（12.5%）、SF3B1（10.4%）、XPO1（8.3%）、MUC2（6.2%）、ATM（4.2%）、FBXW7（4.2%）和BTK（4.2%）。相较于SPEN野生型患者，SPEN突变CLL患者的首次治疗时间显著缩短（2.5年 vs. 4.07年，p=0.01），但多变量分析显示该相关性未保持独立显著性。在多变量分析中，IGHV未突变状态、TP53基因失活及12号染色体三体仍是首次治疗时间缩短的独立预测因素。结论：本研究表明SPEN突变与CLL不良预后相关，建议将SPEN纳入CLL患者预后评估的常规测序检测体系。

原文链接：

Mutational Landscape and Clinical Impact of SPEN Mutations in Patients with Chronic Lymphocytic Leukemia