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Genome Med. 2014 Oct 14;6(10):81. doi: 10.1186/s13073-014-0081-7. eCollection 2014.

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach.

Author information

1
Department of Biomedical Informatics, Vanderbilt University School of Medicine, 2525 West End Avenue, Suite 600, Nashville, TN 37203 USA.
2
Department of Biomedical Informatics, Vanderbilt University School of Medicine, 2525 West End Avenue, Suite 600, Nashville, TN 37203 USA ; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA ; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 USA ; Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232 USA.

Abstract

BACKGROUND:

Recently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.

METHODS:

In this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.

RESULTS:

We found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).

CONCLUSIONS:

This study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.

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