文章：

骨髓增生异常综合征患者总体异常选择性剪接的预后意义

The prognostic significance of global aberrant alternative splicing in patients with myelodysplastic syndrome

原文发布日期：2018-08-13

DOI: 10.1038/s41408-018-0115-2

类型: Article

开放获取: 是

英文摘要：

Aberrant alternative splicing (AS) is a hallmark of cancer development. However, there are limited data regarding its clinical implications in myelodysplastic syndrome (MDS). In this study, we performed an in-depth analysis of global AS in 176 primary MDS patients with 20 normal marrow transplant donors as reference. We found that 26.9% of the expressed genes genome-wide were aberrantly spliced in MDS patients compared with normal donors. These aberrant AS genes were related to pathways involved in cell proliferation, cell adhesion and protein degradation. A higher degree of global aberrant AS was associated with male gender and U2AF1 mutation, and predicted shorter overall survival and time to leukemic change. Moreover, it was an independent unfavorable prognostic factor irrespective of age, revised international prognostic scoring system (IPSS-R) risk, and mutations in SRSF2, ZRSR2, ASXL1, TP53, and EZH2. With LASSO-Cox regression method, we constructed a simple prognosis prediction model composed of 13 aberrant AS genes, and demonstrated that it could well stratify MDS patients into distinct risk groups. To our knowledge, this is the first report demonstrating significant prognostic impacts of aberrant splicing on MDS patients. Further prospective studies in larger cohorts are needed to confirm our observations.

摘要翻译： 

异常选择性剪接是癌症发展的一个标志。然而，关于其在骨髓增生异常综合征中的临床意义的数据有限。在本研究中，我们以20名正常骨髓移植供者为参照，对176例原发性MDS患者进行了全局选择性剪接的深入分析。我们发现，与正常供者相比，MDS患者全基因组范围内26.9%的表达基因存在异常剪接。这些异常剪接基因涉及细胞增殖、细胞粘附和蛋白质降解等相关通路。全局异常剪接程度较高与男性性别和U2AF1突变相关，并预测较短的总生存期和白血病转化时间。此外，无论年龄、修订版国际预后评分系统风险、以及SRSF2、ZRSR2、ASXL1、TP53和EZH2基因突变如何，它都是一个独立的不良预后因素。采用LASSO-Cox回归方法，我们构建了一个由13个异常剪接基因组成的简易预后预测模型，并证明该模型能很好地将MDS患者分层为不同风险组。据我们所知，这是首次报道异常剪接对MDS患者具有显著预后影响的研究。需要在更大队列中进行进一步前瞻性研究以确认我们的观察结果。

原文链接：

The prognostic significance of global aberrant alternative splicing in patients with myelodysplastic syndrome