Systematic characterization of pan-cancer mutation clusters.
Systematic characterization of pan-cancer mutation clusters.
复制标题
DOI：
10.15252/msb.20177974
复制
发表时间：
2018-03-23
影响因子：
9.9
通讯作者：
Boutros M
中科院分区：
文献类型：
--
作者：
Buljan M;Blattmann P;Aebersold R;Boutros M
癌症基因组测序表明，驱动基因通常不仅可以通过升高的突变频率来区分，还可以通过以高速率积累变化的特定核苷酸位置来区分。然而，与残基突变时驱动肿瘤发生的潜力相关的特性尚未得到系统研究。在这里，使用一种新的方法学方法，我们确定和表征了160个人类蛋白质内的180个热点残基的概要，这些蛋白质以显着的频率发生，并且可能具有功能相关的影响。我们发现这样的突变（i）在可以存在于开和关状态的蛋白质中更突出，（ii）反映了肿瘤起源的身份，以及（iii）通常定位在介导与其他蛋白质或配体相互作用的界面内。接下来，我们进一步研究了人类蛋白质复合物的结构数据，并确定了许多以高速率积累癌症突变的其他蛋白质界面。这些分析共同表明，蛋白质相互作用的破坏和失调可能有助于癌症蛋白质的功能转换和激活下游变化。
Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate. However, properties associated with a residue's potential to drive tumorigenesis when mutated have not yet been systematically investigated. Here, using a novel methodological approach, we identify and characterize a compendium of 180 hotspot residues within 160 human proteins which occur with a significant frequency and are likely to have functionally relevant impact. We find that such mutations (i) are more prominent in proteins that can exist in the on and off state, (ii) reflect the identity of a tumor of origin, and (iii) often localize within interfaces which mediate interactions with other proteins or ligands. Following, we further examine structural data for human protein complexes and identify a number of additional protein interfaces that accumulate cancer mutations at a high rate. Jointly, these analyses suggest that disruption and dysregulation of protein interactions can be instrumental in switching functions of cancer proteins and activating downstream changes.