Systematic Analysis of Splice-Site-Creating Mutations in Cancer.
Systematic Analysis of Splice-Site-Creating Mutations in Cancer.
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DOI：
10.1016/j.celrep.2018.03.052
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发表时间：
2018-04-03
期刊：
影响因子：
8.8
通讯作者：
Ding L
中科院分区：
文献类型：
--
作者：
Jayasinghe RG;Cao S;Gao Q;Wendl MC;Vo NS;Reynolds SM;Zhao Y;Climente-González H;Chai S;Wang F;Varghese R;Huang M;Liang WW;Wyczalkowski MA;Sengupta S;Li Z;Payne SH;Fenyö D;Miner JH;Walter MJ;Cancer Genome Atlas Research Network;Vincent B;Eyras E;Chen K;Shmulevich I;Chen F;Ding L
在过去的十年中，癌症基因组研究主要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，我们应用了一种生物信息学工具MiSplice，在8656个TCGA肿瘤中大规模发现了剪接位点产生突变（SCMs）。我们报告了1964个最初错误注释的突变，有明确的证据表明产生了替代剪接。TP53和GATA3分别有26个和18个SCMs， ATRX有5个来自低级别胶质瘤。包括PARP1、BRCA1和BAP1在内的11个基因突变在实验中被证实具有剪接位点创建功能。值得注意的是，我们发现与错义突变相比，SCM诱导的新抗原的免疫原性可能高出几倍，例如复发性GATA3 SCM。此外，PD-1和PD-L1在SCMs肿瘤中高表达，提示免疫阻断治疗的候选物。我们的工作强调了整合DNA和RNA数据对于理解人类疾病突变的功能和临床意义的重要性。Jayasinghe等人从33种癌症类型的8000多个肿瘤样本中鉴定出近2000个剪接位点创建突变（SCMs）。它们为以前错误注释的突变提供了更准确的解释，强调了整合数据类型以理解人类疾病中剪接突变的功能和临床意义的重要性。
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. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously misannotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.
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影响因子：
12.3
作者：
Nielsen M;Andreatta M
通讯作者：
Andreatta M
DOI：
10.1007/s00467-016-3565-4
发表时间：
2017-06
期刊：
Pediatric nephrology (Berlin, Germany)
影响因子：
--
作者：
Malone AF;Funk SD;Alhamad T;Miner JH
通讯作者：
Miner JH
DOI：
10.1007/978-1-60761-759-4_15
发表时间：
2010-01-01
期刊：
CANCER SUSCEPTIBILITY: METHODS AND PROTOCOLS
影响因子：
--
作者：
Gaildrat, Pascaline;Killian, Audrey;Tosi, Mario
通讯作者：
Tosi, Mario
影响因子：
64.8
作者：
通讯作者：
--
ATRX 缺失会促进肿瘤生长并损害神经胶质瘤中的非同源末端连接 DNA 修复。
影响因子：
17.1
作者：
Koschmann C;Calinescu AA;Nunez FJ;Mackay A;Fazal-Salom J;Thomas D;Mendez F;Kamran N;Dzaman M;Mulpuri L;Krasinkiewicz J;Doherty R;Lemons R;Brosnan-Cashman JA;Li Y;Roh S;Zhao L;Appelman H;Ferguson D;Gorbunova V;Meeker A;Jones C;Lowenstein PR;Castro MG
通讯作者：
Castro MG