Journal article
Systematic Analysis of Splice-Site-Creating Mutations in Cancer
Cell reports (Cambridge), Vol.23(1), pp.270-281.e3
04/03/2018
DOI: 10.1016/j.celrep.2018.03.052
PMCID: PMC6055527
PMID: 29617666
Abstract
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.
Details
- Title: Subtitle
- Systematic Analysis of Splice-Site-Creating Mutations in Cancer
- Creators
- Reyka G Jayasinghe - Washington University in St. LouisSong Cao - Washington University in St. LouisQingsong Gao - Washington University in St. LouisMichael C Wendl - Washington University in St. LouisNam Sy Vo - The University of Texas MD Anderson Cancer CenterSheila M Reynolds - Institute for Systems BiologyYanyan Zhao - Washington University in St. LouisHéctor Climente-González - Université Paris Sciences et LettresShengjie Chai - University of North Carolina at Chapel HillFang Wang - The University of Texas MD Anderson Cancer CenterRajees Varghese - Washington University in St. LouisMo Huang - Washington University in St. LouisWen-Wei Liang - Washington University in St. LouisMatthew A Wyczalkowski - Washington University in St. LouisSohini Sengupta - Washington University in St. LouisZhi Li - York UniversitySamuel H Payne - Pacific Northwest National LaboratoryDavid Fenyö - York UniversityJeffrey H Miner - Washington University in St. LouisMatthew J Walter - Washington University in St. LouisBenjamin Vincent - University of North Carolina at Chapel HillEduardo Eyras - Universitat Pompeu FabraKen Chen - The University of Texas MD Anderson Cancer CenterIlya Shmulevich - Institute for Systems BiologyFeng Chen - Washington University in St. LouisLi Ding - Washington University in St. Louis
- Contributors
- Cancer Genome Atlas Research Network (Author)Deqin Ma (Author) - University of Iowa, PathologyMohammed M Milhem (Author) - University of Iowa, Internal MedicineAaron D Bossler (Author) - University of Iowa, Pathology
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.23(1), pp.270-281.e3
- DOI
- 10.1016/j.celrep.2018.03.052
- PMID
- 29617666
- PMCID
- PMC6055527
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- U24 CA143843 / NCI NIH HHS R01 CA180006 / NCI NIH HHS P30 CA016086 / NCI NIH HHS U24 CA210972 / NCI NIH HHS R01 CA178383 / NCI NIH HHS U24 CA210957 / NCI NIH HHS U54 HG003079 / NHGRI NIH HHS P30 CA016672 / NCI NIH HHS U24 CA143883 / NCI NIH HHS U24 CA210990 / NCI NIH HHS U24 CA143799 / NCI NIH HHS R01 HG009711 / NHGRI NIH HHS U24 CA143867 / NCI NIH HHS U24 CA143858 / NCI NIH HHS U24 CA143882 / NCI NIH HHS U54 HG003067 / NHGRI NIH HHS U24 CA143845 / NCI NIH HHS U24 CA143835 / NCI NIH HHS U54 HG003273 / NHGRI NIH HHS U24 CA143840 / NCI NIH HHS U24 CA211006 / NCI NIH HHS U24 CA144025 / NCI NIH HHS U24 CA143866 / NCI NIH HHS U24 CA210950 / NCI NIH HHS U24 CA143848 / NCI NIH HHS R01 CA163722 / NCI NIH HHS
- Language
- English
- Date published
- 04/03/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Internal Medicine
- Record Identifier
- 9984183983002771
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