Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations.
Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations.
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鉴定癌症类型的显着突变区域的鉴定突出了功能分子改变的丰富景观。
DOI：
10.1038/ng.3471
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发表时间：
2016-02
期刊：
影响因子：
30.8
通讯作者：
Greenleaf WJ
中科院分区：
文献类型：
--
作者：
Araya CL;Cenik C;Reuter JA;Kiss G;Pande VS;Snyder MP;Greenleaf WJ
癌症测序研究主要通过蛋白质改变突变的积累来识别癌症驱动基因。一种改进的方法将是注释独立的，对蛋白质内未知的功能分布敏感，并包括非编码驱动程序。我们在21种肿瘤类型中采用基于密度的聚类方法来检测可变大小的显著突变区域（SMR）。SMR揭示了一系列编码和非编码元件的复发性改变，包括转录因子结合位点和非翻译区，在高达15%的特定肿瘤类型中突变。SMR揭示了分子结构域和界面处突变的空间聚集，通常伴随着信号传导的相关变化。SMR中的突变频率表明，不同的蛋白质区域在肿瘤类型之间发生差异性突变，如PIK3CA的接头区域所示，其中生物物理模拟表明突变影响调控相互作用。SMR的功能多样性强调了致癌误调节的不同机制和功能不可知驱动识别的优势。
Cancer sequencing studies have primarily identified cancer-driver genes by the accumulation of protein-altering mutations. An improved method would be annotation-independent, sensitive to unknown distributions of functions within proteins, and inclusive of non-coding drivers. We employed density-based clustering methods in 21 tumor types to detect variably-sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and non-coding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼15% of specific tumor types. SMRs reveal spatial clustering of mutations at molecular domains and interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated among tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally-agnostic driver identification.