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Comprehensive assessment of cancer missense mutation clustering in protein structures
- Source :
- Proceedings of the National Academy of Sciences. 112
- Publication Year :
- 2015
- Publisher :
- Proceedings of the National Academy of Sciences, 2015.
-
Abstract
- Large-scale tumor sequencing projects enabled the identification of many new cancer gene candidates through computational approaches. Here, we describe a general method to detect cancer genes based on significant 3D clustering of mutations relative to the structure of the encoded protein products. The approach can also be used to search for proteins with an enrichment of mutations at binding interfaces with a protein, nucleic acid, or small molecule partner. We applied this approach to systematically analyze the PanCancer compendium of somatic mutations from 4,742 tumors relative to all known 3D structures of human proteins in the Protein Data Bank. We detected significant 3D clustering of missense mutations in several previously known oncoproteins including HRAS, EGFR, and PIK3CA. Although clustering of missense mutations is often regarded as a hallmark of oncoproteins, we observed that a number of tumor suppressors, including FBXW7, VHL, and STK11, also showed such clustering. Beside these known cases, we also identified significant 3D clustering of missense mutations in NUF2, which encodes a component of the kinetochore, that could affect chromosome segregation and lead to aneuploidy. Analysis of interaction interfaces revealed enrichment of mutations in the interfaces between FBXW7-CCNE1, HRAS-RASA1, CUL4B-CAND1, OGT-HCFC1, PPP2R1A-PPP2R5C/PPP2R2A, DICER1-Mg2+, MAX-DNA, SRSF2-RNA, and others. Together, our results indicate that systematic consideration of 3D structure can assist in the identification of cancer genes and in the understanding of the functional role of their mutations.
- Subjects :
- Models, Molecular
Mutation, Missense
STK11
Cell Cycle Proteins
Biology
Chromosome segregation
Protein structure
Catalytic Domain
Neoplasms
Protein Interaction Mapping
medicine
Cluster Analysis
Humans
Missense mutation
Genetic Predisposition to Disease
Protein Interaction Maps
HRAS
Databases, Protein
Cluster analysis
Oncogene Proteins
Genetics
Multidisciplinary
Cancer
computer.file_format
medicine.disease
Protein Data Bank
Protein Structure, Tertiary
PNAS Plus
computer
Algorithms
Protein Binding
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....279f347a40494557adf59edde231a9d8