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A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes.


ABSTRACT: Exitron splicing (EIS) creates a cryptic intron (called an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered that EIS affected 63% of human coding genes and that 95% of those events were tumor specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations in their affected genes. Functionally, we discovered that EIS altered known and novel cancer driver genes for causing gain- or loss-of-function, which promotes tumor progression. Importantly, we identified EIS-derived neoepitopes that bind to major histocompatibility complex (MHC) class I or II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed an association between EIS-derived neoantigen load and checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.

SUBMITTER: Wang TY 

PROVIDER: S-EPMC8141048 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes.

Wang Ting-You TY   Liu Qi Q   Ren Yanan Y   Alam Sk Kayum SK   Wang Li L   Zhu Zhu Z   Hoeppner Luke H LH   Dehm Scott M SM   Cao Qi Q   Yang Rendong R  

Molecular cell 20210415 10


Exitron splicing (EIS) creates a cryptic intron (called an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered that EIS affected 63% of human coding genes and that 95% of those events were tumor specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations  ...[more]

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