Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Division of Oncology, Washington University in St. Louis, St. Louis, MO 63110, USA.
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Division of Oncology, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63130, USA.
Cell Rep. 2018 Apr 3;23(1):270-281.e3. doi: 10.1016/j.celrep.2018.03.052.
For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.
在过去的十年中，癌症基因组研究一直集中在导致剪接位点破坏的突变上，而忽略了那些具有剪接产生潜力的突变。在这里，我们应用了一种名为 MiSplice 的生物信息学工具，在 8656 个 TCGA 肿瘤中大规模发现剪接位点产生突变（SCMs）。我们报告了 1964 个最初被错误注释的突变，这些突变有明确的证据表明它们可以产生替代的剪接接头。TP53 和 GATA3 分别有 26 和 18 个 SCM，而 ATRX 则有 5 个来自低级别胶质瘤。包括 PARP1、BRCA1 和 BAP1 在内的 11 个基因的突变被实验验证具有剪接位点产生功能。值得注意的是，我们发现由 SCM 诱导的新抗原比错义突变更具免疫原性，GATA3 的 SCM 就是一个例子。此外，我们还观察到 SCM 肿瘤中 PD-1 和 PD-L1 的高表达，提示了免疫阻断治疗的候选药物。我们的工作强调了整合 DNA 和 RNA 数据对于理解人类疾病中突变的功能和临床意义的重要性。
