Gain and loss of phosphorylation sites in human cancer
Gain and loss of phosphorylation sites in human cancer
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DOI：
10.1093/bioinformatics/btn267
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发表时间：
2008-08-15
期刊：
影响因子：
5.8
通讯作者：
Mooney, Sean D.
中科院分区：
文献类型：
--
作者：
Radivojac, Predrag;Baenziger, Peter H.;Mooney, Sean D.
动机：人类基因的编码区突变导致了一系列疾病和表型。在已经被广泛研究的病变中，有几个被致病突变破坏的生化功能的洞察力。目前，在人类基因突变数据库(HGMD，2007年8月)中登记的与遗传病相关的编码区突变超过60000个，在数据库SNP(DBSNP，Build 127)中记录的多态氨基酸替换超过70000个。了解这些变异对临床表型的作用和机制是一个艰巨的问题。结果：在这项研究中，我们研究了磷酸化在体细胞癌突变和遗传性疾病中的作用。与我们的对照数据集(假定是中性的nsSNPs和随机氨基酸替换)相比，体细胞癌突变数据集被证明具有显著的丰富性，无法丰富导致磷酸化增强或丢失的突变。在体细胞癌突变中，激酶基因中的那些突变代表了一组最丰富的突变，这些突变破坏了磷酸化位点，表明磷酸化靶点突变是磷酸化去调控的一个积极原因。总体而言，这一证据表明，靶蛋白中磷酸化位点的获得和丢失可能是预测致癌突变的重要特征，并可能代表一些遗传和体细胞突变的分子病因。
Motivation: Coding-region mutations in human genes are responsible for a diverse spectrum of diseases and phenotypes. Among lesions that have been studied extensively, there are insights into several of the biochemical functions disrupted by disease-causing mutations. Currently, there are more than 60 000 coding-region mutations associated with inherited disease catalogued in the Human Gene Mutation Database (HGMD, August 2007) and more than 70 000 polymorphic amino acid substitutions recorded in dbSNP (dbSNP, build 127). Understanding the mechanism and contribution these variants make to a clinical phenotype is a formidable problem.Results: In this study, we investigate the role of phosphorylation in somatic cancer mutations and inherited diseases. Somatic cancer mutation datasets were shown to have a signi.cant enrichment for mutations that cause gain or loss of phosphorylation when compared to our control datasets (putatively neutral nsSNPs and random amino acid substitutions). Of the somatic cancer mutations, those in kinase genes represent the most enriched set of mutations that disrupt phosphorylation sites, suggesting phosphorylation target site mutation is an active cause of phosphorylation deregulation. Overall, this evidence suggests both gain and loss of a phosphorylation site in a target protein may be important features for predicting cancercausing mutations and may represent a molecular cause of disease for a number of inherited and somatic mutations.