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A BAP1 synonymous mutation results in exon skipping, loss of function and worse patient prognosis

ABSTRACT: Summary Synonymous mutations are generally disregarded by genomic analyses because they are considered non-pathogenic. We identified and characterized a somatic synonymous mutation in the epigenetic modifier and tumor suppressor BAP1, resulting in exon skipping and complete protein inactivation. This radically altered the prognosis of a clear-cell renal cell carcinoma patient from The Cancer Genome Atlas (TCGA) with a PBRM1 mutation (a predictor biomarker for positive responses to immune checkpoint inhibitors) from good (an estimated overall survival of 117 months) to a very bad prognosis (an estimated overall survival of 31 months), emphasizing the importance of scrutinizing synonymous mutations near acceptor splice sites of cancer genes for accurate precision medicine. Graphical abstract Highlights • First synonymous BAP1 mutation that leads to exon skipping and loss of function• Exon 11 skipping is a hotspot for BAP1 inactivation• First synonymous mutation reported to reduce fourfold the expected patient survival• Synonymous mutations can inactivate cancer genes and affect patient prognosis Human genetics; genetics; cancer; KIRC-TCGA; personalized medicine

SUBMITTER: Niersch J

PROVIDER: S-EPMC7918674 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.

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