Integrative and quantitative analysis of disease mutations in the RAS-RAF-MEK-ERK pathway and implications for personalized medicine
Jul 18, 2016 1239 views 
The Ras/MAPK syndromes ('RASopathies') are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen-activated protein kinase (MAPK) pathway. It is intriguing that mutations in the same 15 genes are also frequently identified in different types of human cancers. In this talk, I will shed light on 956 RASopathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures [1]. Using the protein design algorithm FoldX and mathematical network modelling, we show that quantitative rather than qualitative network differences determine the phenotypic outcome of RASopathy compared to cancer mutations. Furthermore, our quantitative predictions can explain why some cancer mutations (‘drivers’) occur at significantly higher rates than - presumably - functionally alternative mutations. For example, V600E in the BRAF hydrophobic activation segment (AS) pocket accounts for >95% of all kinase mutations. We used experimental and in silico structure-energy statistical analyses, to elucidate why the V600E mutation, but no other mutation at this, or any other positions in BRAF's hydrophobic pocket, is predominant. We find that oncogene mutations frequencies depend on the equilibrium between the destabilization of the hydrophobic pocket, the overall folding energy, the activation of the kinase and the number of bases required to change the corresponding amino acid [2]. Using a random forest classifier, we quantitatively dissected the parameters contributing to BRAF AS cancer frequencies. These findings can be applied to genome-wide association studies and prediction models. [1] Kiel C, Serrano L. Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Mol Syst Biol. 2014 May 6;10:727 [2] Kiel C, Benisty H, Lloréns-Rico V, Serrano L. The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF. Elife. 2016 Jan 8;5. pii: e12814.