文章：

从华氏巨球蛋白血症到侵袭性弥漫大B细胞淋巴瘤：导致转化的异常的全外显子组分析

Alternative splicing discriminates molecular subtypes and has prognostic impact in diffuse large B-cell lymphoma

原文发布日期：2017-08-25

DOI: 10.1038/bcj.2017.71

类型: Original Article

开放获取: 是

英文摘要：

Effect of alternative splicing (AS) on diffuse large B-cell lymphoma (DLBCL) pathogenesis and survival has not been systematically addressed. Here, we compared differentially expressed genes and exons in association with survival after chemoimmunotherapy, and between germinal center B-cell like (GCB) and activated B-cell like (ABC) DLBCLs. Genome-wide exon array-based screen was performed from samples of 38 clinically high-risk patients who were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. The exon expression profile separated the patients according to molecular subgroups and survival better than the gene expression profile. Pathway analyses revealed enrichment of AS genes in inflammation and adhesion-related processes, and in signal transduction, such as phosphatidylinositol signaling system and adenosine triphosphate binding cassette transporters. Altogether, 49% of AS-related exons were protein coding, and domain prediction showed 28% of such exons to include a functional domain, such as transmembrane helix domain or phosphorylation sites. Validation in an independent cohort of 92 DLBCL samples subjected to RNA-sequencing confirmed differential exon usage of selected genes and association of AS with molecular subtypes and survival. The results indicate that AS events are able to discriminate GCB and ABC DLBCLs and have prognostic impact in DLBCL.

摘要翻译： 

可变剪接（AS）对弥漫性大B细胞淋巴瘤（DLBCL）发病机制及生存的影响尚未得到系统性研究。本研究通过比较化疗免疫治疗后生存情况相关的差异表达基因和外显子，以及生发中心B细胞样（GCB）与活化B细胞样（ABC）DLBCL亚型之间的差异，进行了全基因组外显子芯片筛查。样本来自38例接受北欧II期研究中剂量密集化疗免疫治疗及中枢神经系统预防的高危患者。外显子表达谱在区分分子亚型和预测生存方面优于基因表达谱。通路分析显示AS基因富集于炎症、粘附相关过程及信号转导通路（如磷脂酰肌醇信号系统和腺苷三磷酸结合盒转运体）。总计49%的AS相关外显子具有蛋白质编码功能，结构域预测显示其中28%包含功能结构域（如跨膜螺旋结构域或磷酸化位点）。在92例DLBCL样本的独立队列中通过RNA测序验证，确认了特定基因的差异外显子使用及其与分子亚型和生存的关联。结果表明AS事件能够区分GCB与ABC DLBCL亚型，并对DLBCL具有预后指示意义。

原文链接：

Alternative splicing discriminates molecular subtypes and has prognostic impact in diffuse large B-cell lymphoma