1. 3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets
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Chris Sander, Hongxin Zhang, Nikolaus Schultz, Barry S. Taylor, Jianjiong Gao, Brooke E. Sylvester, Selcuk Onur Sumer, Hannah C. Johnsen, Matthew T. Chang, David B. Solit, and Sizhi Paul Gao
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rac1 GTP-Binding Protein ,0301 basic medicine ,DNA Mutational Analysis ,MAP Kinase Kinase 1 ,Method ,Genomics ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Protein structures ,Neoplasms ,MAP2K1 ,Cancer genomics ,medicine ,Genetics ,Humans ,Exome ,Genetics(clinical) ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,Mutation ,Precision medicine ,Driver mutations ,Cancer ,medicine.disease ,Human genetics ,Neoplasm Proteins ,Protein Structure, Tertiary ,3. Good health ,030104 developmental biology ,Molecular Medicine - Abstract
Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0393-x) contains supplementary material, which is available to authorized users.
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