Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts.
Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts.
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DOI：
10.1056/nejmoa1103283
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发表时间：
2011-10-13
期刊：
影响因子：
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通讯作者：
Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
中科院分区：
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作者：
Papaemmanuil E;Cazzola M;Boultwood J;Malcovati L;Vyas P;Bowen D;Pellagatti A;Wainscoat JS;Hellstrom-Lindberg E;Gambacorti-Passerini C;Godfrey AL;Rapado I;Cvejic A;Rance R;McGee C;Ellis P;Mudie LJ;Stephens PJ;McLaren S;Massie CE;Tarpey PS;Varela I;Nik-Zainal S;Davies HR;Shlien A;Jones D;Raine K;Hinton J;Butler AP;Teague JW;Baxter EJ;Score J;Galli A;Della Porta MG;Travaglino E;Groves M;Tauro S;Munshi NC;Anderson KC;El-Naggar A;Fischer A;Mustonen V;Warren AJ;Cross NC;Green AR;Futreal PA;Stratton MR;Campbell PJ;Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
骨髓增生异常综合征是一种多样而常见的慢性血液系统癌症。新的遗传病变的鉴定可以促进新的诊断和治疗策略。我们使用大规模平行测序技术来鉴定9例轻度骨髓增生异常患者基因组中所有蛋白编码外显子的体细胞获得性点突变。对编码RNA剪接因子3B亚基1（SF3B1）的基因进行靶向重测序，也在2087例髓样或其他癌症患者的队列中进行。我们在9例患者中发现了64个点突变。在SF3B1中鉴定了复发性体细胞获得性突变。随访显示，354例骨髓增生异常综合征患者中有72例（20%）发生SF3B1突变，其中以环形铁粒幼细胞为特征的患者发生频率特别高（82例中有53例[65%]）。该基因也在1%至5%的其他肿瘤类型患者中发生突变。所观察到的突变比基于偶然性所预期的有害性更小，这表明突变的蛋白质保留了结构完整性并改变了功能。SF3B1突变与关键基因网络的下调相关，包括核心线粒体途径。在临床上，与无SF3B1突变的患者相比，SF3B1突变的患者血细胞减少较少，无事件生存期较长。SF3B1基因突变提示骨髓增生异常综合征发病机制中信使RNA剪接异常（由Wellcome Trust和其他机构资助。
Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.)