Intron retention is a widespread mechanism of tumor-suppressor inactivation
Intron retention is a widespread mechanism of tumor-suppressor inactivation
复制标题
DOI：
10.1038/ng.3414
复制
发表时间：
2015-11-01
期刊：
影响因子：
30.8
通讯作者：
Lee, Eunjung
中科院分区：
文献类型：
--
作者：
Jung-, Hyunchul;Lee, Donghoon;Lee, Eunjung
相当一部分致病突变是通过异常剪接致病的。尽管基因组分析研究已经确定了癌症中的体细胞单核苷酸变异（SNV），但这些变异引发异常剪接的程度尚未得到系统性研究。在这里，我们分析了来自1，812名癌症患者的RNA测序和外显子组数据，并确定了类似于900个破坏剪接的体细胞外显子SNV。至少有163个SNV（包括31个同义SNV）以等位基因特异性方式引起内含子保留或外显子跳跃，其中约70%的SNV发生在外显子的最后一个碱基上。值得注意的是，引起内含子保留的SNV在肿瘤抑制子中富集，并且这些SNV中的97%产生提前终止密码子，导致通过无义介导的衰变或截短的蛋白质丧失功能。我们还表征了预测这种剪接缺陷的基因组特征。总之，这项工作表明，内含子保留是一种常见的机制，肿瘤抑制基因失活。
A substantial fraction of disease-causing mutations are pathogenic through aberrant splicing. Although genome profiling studies have identified somatic single-nucleotide variants (SNVs) in cancer, the extent to which these variants trigger abnormal splicing has not been systematically examined. Here we analyzed RNA sequencing and exome data from 1,812 patients with cancer and identified similar to 900 somatic exonic SNVs that disrupt splicing. At least 163 SNVs, including 31 synonymous ones, were shown to cause intron retention or exon skipping in an allele-specific manner, with similar to 70% of the SNVs occurring on the last base of exons. Notably, SNVs causing intron retention were enriched in tumor suppressors, and 97% of these SNVs generated a premature termination codon, leading to loss of function through nonsense-mediated decay or truncated protein. We also characterized the genomic features predictive of such splicing defects. Overall, this work demonstrates that intron retention is a common mechanism of tumor-suppressor inactivation.