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RAS-RAF-MEK-ERK通路疾病突变的综合定量分析及其对个体化治疗的意义Integrative and quantitative analysis of disease mutations in the RAS-RAF-MEK-ERK pathway and implications for personalized medicine |
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| 课程网址: | http://videolectures.net/ESHGsymposium2016_serrano_disease_mutati... |
| 主讲教师: | Luis Serrano |
| 开课单位: | 基因组调控中心 |
| 开课时间: | 2016-07-18 |
| 课程语种: | 英语 |
| 中文简介: |  |
| 课程简介: | 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. |
| 关 键 词: | Ras/MAPK综合征; 突变分析; 数学网络建模 |
| 课程来源: | 视频讲座网 |
| 数据采集: | 2021-12-24：zkj |
| 最后编审: | 2021-12-24：zkj |
| 阅读次数: | 79 |