The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors

Molecular Cancer

Research

José M Duarte¹  Seon-Hi J Jang²  Hans Lehrach³  Christoph Wierling³  Bodo MH Lange³  Henning Stehr⁴  Michael Lappe⁴ 

[1] Biomolecular Research, Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, PSI, Switzerland;Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany;Department of Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195, Berlin, Germany;Department of Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195, Berlin, Germany;Max-Planck Institute for Molecular Genetics, Structural Proteomics/Bioinformatics Group, Otto-Warburg Laboratory, Boltzmannstrasse 12, 14195, Berlin, Germany;

关键词: Tumor Suppressor;    Spatial Cluster;    Functional Site;    Linear Classifier;    Driver Mutation;   

DOI  :  10.1186/1476-4598-10-54

 received in 2011-01-17, accepted in 2011-05-16,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundCurrent large-scale cancer sequencing projects have identified large numbers of somatic mutations covering an increasing number of different cancer tissues and patients. However, the characterization of these mutations at the structural and functional level remains a challenge.ResultsWe present results from an analysis of the structural impact of frequent missense cancer mutations using an automated method. We find that inactivation of tumor suppressors in cancer correlates frequently with destabilizing mutations preferably in the core of the protein, while enhanced activity of oncogenes is often linked to specific mutations at functional sites. Furthermore, our results show that this alteration of oncogenic activity is often associated with mutations at ATP or GTP binding sites.ConclusionsWith our findings we can confirm and statistically validate the hypotheses for the gain-of-function and loss-of-function mechanisms of oncogenes and tumor suppressors, respectively. We show that the distinct mutational patterns can potentially be used to pre-classify newly identified cancer-associated genes with yet unknown function.

【 授权许可】

Unknown   
© Stehr et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.