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Brief Bioinform. 2017 May 1;18(3):413-425. doi: 10.1093/bib/bbw037.

Impacts of somatic mutations on gene expression: an association perspective.

Abstract

Assessing the functional impacts of somatic mutations in cancer genomes is critical for both identifying driver mutations and developing molecular targeted therapies. Currently, it remains a fundamental challenge to distinguish the patterns through which mutations execute their biological effects and to infer biological mechanisms underlying these patterns. To this end, we systematically studied the association between somatic mutations in protein-coding regions and expression profiles, which represents an indirect measurement of impacts. We defined mutation features (mutation type, cluster and status) and built linear regression models to assess mutation associations with mRNA expression and protein expression. Our results presented a comprehensive landscape of the associations between mutation features and expression profile in multiple cancer types, including 62 genes showing mutation type associated expression changes, 21 genes showing mutation cluster associations and 51 genes showing mutation status associations. We revealed four characteristics of the patterns that mutations impact on expression. First, we showed that mutation type (truncation versus amino acid-altering mutations) was the most important determinant of expression levels. Second, we detected mutation clusters in well-studied oncogenes that were associated with gene expression. Third, we found both similarities and differences in association patterns existed within and across cancer types. Fourth, although many of the observed associations stay stable at both mRNA and protein expression levels, there are also novel associations uniquely observed at the protein level, which warrant future investigation. Taken together, our findings provided implications for cancer driver gene prioritization and insights into the functional consequences of somatic mutations.

KEYWORDS:

cancer gene; gene expression; mutation cluster; mutation type; somatic mutation

PMID:
27127206
PMCID:
PMC5862283
DOI:
10.1093/bib/bbw037
[Indexed for MEDLINE]
Free PMC Article

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