Jayasinghe, Reyka G; Cao, Song; Gao, Qingsong; Wendl, Michael C; Vo, Nam Sy; Reynolds, Sheila M; Zhao, Yanyan; Climente-González, Héctor; Chai, Shengjie; Wang, Fang; Varghese, Rajees; Huang, Mo; Liang, Wen-Wei; Wyczalkowski, Matthew A; Sengupta, Sohini; Li, Zhi; Payne, Samuel H; Fenyö, David; Miner, Jeffrey H; Walter, Matthew J; ... (2018). Systematic Analysis of Splice-Site-Creating Mutations in Cancer. Cell reports, 23(1), 270-281.e3. Cell Press 10.1016/j.celrep.2018.03.052
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nihms958979.pdf - Accepted Version Available under License Creative Commons: Attribution (CC-BY). Download (2MB) | Preview |
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1-s2.0-S2211124718303978-main.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (10MB) | Preview |
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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2211-1247 |
Publisher: |
Cell Press |
Language: |
English |
Submitter: |
Marla Rittiner |
Date Deposited: |
09 Oct 2019 10:37 |
Last Modified: |
23 Oct 2019 18:20 |
Publisher DOI: |
10.1016/j.celrep.2018.03.052 |
PubMed ID: |
29617666 |
Additional Information: |
Mark Rubin (Direktor DBMR) ist Collaborator in dieser Publikation. |
Uncontrolled Keywords: |
RNA mutations of clinical relevance splicing |
BORIS DOI: |
10.7892/boris.126382 |
URI: |
https://boris.unibe.ch/id/eprint/126382 |
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