Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes
Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes
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DOI：
10.1002/cncr.33745
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发表时间：
2021-06-23
期刊：
影响因子：
6.2
通讯作者：
Garcia-Manero, Guillermo
中科院分区：
文献类型：
--
作者：
Kanagal-Shamanna, Rashmi;Montalban-Bravo, Guillermo;Garcia-Manero, Guillermo
背景骨髓增生异常综合征（MDS）中的SF 3B 1突变（SF 3B 1（mut））常涉及密码子K700 E，预后良好。非K700 E SF 3B 1（mut）的预后作用尚不确定。方法：作者分析了94例初治SF 3B 1（mut）MDS患者（18%）和415例初治SF 3B 1（wt）MDS患者的临床病理特征和结局，并探讨了K700 E和非K700 E SF 3B 1（mut）MDS之间的差异。结果55例患者（59%）携带K700 E。复发性非K700 E突变（39例[41%]）包括R625、H662和K666。与SF 3B 1（mut）K700 E患者相比，非K700 E患者的中性粒细胞绝对计数中位数较低（1.8 vs 2.4; P = 0.005），并且根据修订的国际预后评分系统（19% vs 4%; P = 0.031），中性粒细胞绝对计数中位数通常较高。非K700 E MDS通常与RUNX 1相关（26% vs 7%; P = .012），仅与BCOR、IDH 2和SRSF 2突变相关。剪接分析显示K700和非K700 E MDS患者之间的选择性剪接事件和基因表达谱的差异分布。大多数（至少80%）SF 3B 1（mut）K700 E、SF 3B 1（mut）非K700 E和SF 3B 1（wt）患者接受了低甲基化药物治疗。中位随访16个月后，在所有MDS患者（未达到vs 25.2个月; P = .0003）、低级别MDS患者和骨髓增生异常综合征伴环形铁粒幼细胞（MDS-RS）患者中，SF 3B 1（mut）的总生存期（OS）上级SF 3B 1（wt）。与SF 3B 1（wt）相比，SF 3B 1（mut）K700 E在所有MDS中具有上级结局（中位OS，25个月vs未达到; P = .0001），在低级别MDS中（中位OS，41.3个月vs未达到; P = .0015），在MDS-RS中（中位OS，22.3个月vs未达到; P = 0.0001），但在非K700 E和SF 3B 1（wt）MDS之间未观察到显著差异。通过多因素分析，SF 3B 1（mut）K700 E突变的缺失与预后独立相关。结论SF 3B 1突变亚型在MDS危险性评估中的重要性。摘要世界卫生组织和骨髓增生异常综合征预后国际工作组认为SF 3B 1突变的骨髓增生异常综合征（MDS）预后良好。然而，这篇文章表明，只有SF 3B 1 K700 E突变的MDS患者预后良好（而不是SF 3B 1突变涉及其他密码子的MDS患者）。这对完善未来MDS子分类和风险评估标准具有重要意义。
Background SF3B1 mutations (SF3B1(mut)) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1(mut) is uncertain. METHODS The authors analyzed the clinicopathological features and outcomes of a single-institution series of 94 treatment-naive SF3B1(mut) MDS patients (18%) and 415 treatment-naive SF3B1(wt) MDS patients and explored the differences between K700E and non-K700E SF3B1(mut) MDS. Results Fifty-five patients (59%) carried K700E. Recurrent non-K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1(mut) K700E patients, non-K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P = .005) and were frequently "high" according to the Revised International Prognostic Scoring System (19% vs 4%; P = .031). Non-K700E MDS was associated frequently with RUNX1 (26% vs 7%; P = .012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non-K700E MDS patients. The majority (at least 80%) of SF3B1(mut) K700E, SF3B1(mut) non-K700E, and SF3B1(wt) patients were treated with hypomethylating agents. Over a median follow-up of 16 months, SF3B1(mut) had superior overall survival (OS) in comparison with SF3B1(wt) in all MDS patients (not reached vs 25.2 months; P = .0003), in patients with low-grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS). Compared with SF3B1(wt), SF3B1(mut) K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P = .0001), in low-grade MDS (median OS, 41.3 months vs not reached; P = .0015), and in MDS-RS (median OS, 22.3 months vs not reached; P = .0001), but no significant difference was seen between non-K700E and SF3B1(wt) MDS. By multivariable analysis, the absence of SF3B1(mut) K700E mutations was independently associated with the prognosis. Conclusions This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment. LAY SUMMARY Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes. However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons). This has important implications for refining future MDS subclassification and risk assessment criteria.