SF3B1 mutations constitute a novel therapeutic target in breast cancer.
SF3B1 mutations constitute a novel therapeutic target in breast cancer.
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DOI：
10.1002/path.4483
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发表时间：
2015-03
期刊：
影响因子：
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通讯作者：
Natrajan RC
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文献类型：
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作者：
Maguire SL;Leonidou A;Wai P;Marchiò C;Ng CK;Sapino A;Salomon AV;Reis-Filho JS;Weigelt B;Natrajan RC
已发现编码参与RNA剪接的蛋白质的基因突变在几种肿瘤类型中以相对高的频率发生，包括骨髓增生异常综合征、慢性淋巴细胞白血病、葡萄膜黑色素瘤和胰腺癌，而在乳腺癌中以较低的频率发生。为了研究RNA剪接功能障碍是否与乳腺癌的发病机制有关，我们对已发表的外显子组和全基因组测序数据进行了重新分析。该分析显示，剪接体组分基因的突变发生在5.6%的乳腺癌中，包括SF3B1基因的热点突变，其在1.8%的乳腺癌中发现。SF3B1突变与ER阳性疾病、AKT1突变和不同的拷贝数改变显著相关。在一组特殊的乳腺癌组织学亚型中对热点突变的额外分析显示，16%和6%的乳腺乳头状癌和粘液癌携带SF3B1 K700E突变。RNA测序鉴定了在具有SF3B1突变的肿瘤中表达的差异剪接事件，包括蛋白质编码基因TMEM 14 C、RPL 31、DYNL11、UQCC和ABCC 5以及长非编码RNA CRNDE。此外，发现SF3B1突变细胞系对SF3b复合物抑制剂spliceostatin A敏感，并且处理导致剪接特征的扰动。尽管罕见，但SF3B1突变导致选择性剪接事件，并可能构成乳腺癌亚组中的驱动因素和新的治疗靶点。© 2014作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.