ArticleHuman mutation2012
Oncogenic potential is related to activating effect of cancer single and double somatic mutations in receptor tyrosine kinases.
Article in Human mutation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Review
- PremPS: Predicting the impact of missense mutations on protein stability.PLoS computational biology · 2020Article
- Limitations and challenges in protein stability prediction upon genome variations: towards future applications in precision medicine.Computational and structural biotechnology journal · 2020Review
- Effect of double mutations T790M/L858R on conformation and drug-resistant mechanism of epidermal growth factor receptor explored by molecular dynamics simulations.RSC advances · 2018Article
- Mutational signatures and mutable motifs in cancer genomes.Briefings in bioinformatics · 2018Review
- Computational Approaches to Prioritize Cancer Driver Missense Mutations.International journal of molecular sciences · 2018Review
- Computational and Experimental Characterization of Patient Derived Mutations Reveal an Unusual Mode of Regulatory Spine Assembly and Drug Sensitivity in EGFR Kinase.Biochemistry · 2017Article
- Annotating Mutational Effects on Proteins and Protein Interactions: Designing Novel and Revisiting Existing Protocols.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation.Cancer research · 2016Article
- ProKinO: a unified resource for mining the cancer kinome.Human mutation · 2015Article
- Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors.Scientific reports · 2014Article
- Predicting the Impact of Missense Mutations on Protein-Protein Binding Affinity.Journal of chemical theory and computation · 2014Article
- Prediction and prioritization of rare oncogenic mutations in the cancer Kinome using novel features and multiple classifiers.PLoS computational biology · 2014Article
- A graph theoretic approach to utilizing protein structure to identify non-random somatic mutations.BMC bioinformatics · 2014Article
- The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer.PLoS computational biology · 2014Article
- Molecular mechanisms of disease-causing missense mutations.Journal of molecular biology · 2013Review
- Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Aberrant activation of receptor tyrosine kinases (RTKs) is a common feature of many cancer cells. It was previously suggested that the mechanisms of kinase activation in cancer might be linked to transitions between active and inactive states. Here, we estimate the effects of single and double cancer mutations on the stability of active and inactive states of the kinase domains from different RTKs. We show that singleton cancer mutations destabilize active and inactive states; however, inactive states are destabilized more than the active ones, leading to kinase activation. We show that there exists a relationship between the estimate of oncogenic potential of cancer mutation and kinase activation. Namely, more frequent mutations have a higher activating effect, which might allow us to predict the activating effect of the mutations from the mutation spectra. Independent evolutionary analysis of mutation spectra complements this observation and finds the same frequency threshold defining mutation hotspots. We analyze double mutations and report a positive epistasis and additional advantage of doublets with respect to cancer cell fitness. The activation mechanisms of double mutations differ from those of single mutations and double mutation spectrum is found to be dissimilar to the mutation spectrum of singletons.
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Registered trials
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