Fredriksson Nils Johan, Elliott Kerryn, Filges Stefan, Van den Eynden Jimmy, Ståhlberg Anders, Larsson Erik
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
PLoS Genet. 2017 May 10;13(5):e1006773. doi: 10.1371/journal.pgen.1006773. eCollection 2017 May.
Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as influence on gene expression has been more elusive. Here, we show that frequently recurring promoter mutations in melanoma occur almost exclusively at cytosines flanked by a distinct sequence signature, TTCCG, with TERT as a notable exception. In active, but not inactive, promoters, mutation frequencies for cytosines at the 5' end of this ETS-like motif were considerably higher than expected based on a UV trinucleotide mutational signature. Additional analyses solidify this pattern as an extended context-specific mutational signature that mediates an exceptional position-specific vulnerability to UV mutagenesis, arguing against positive selection. We further use ultra-sensitive amplicon sequencing to demonstrate that cell cultures exposed to UV light quickly develop subclonal mutations specifically in affected positions. Our findings have implications for the interpretation of somatic mutations in regulatory regions, and underscore the importance of genomic context and extended sequence patterns to accurately describe mutational signatures in cancer.
对整个肿瘤基因组进行测序有望揭示功能性体细胞调节突变，比如端粒酶逆转录酶（TERT）启动子中所描述的那些突变。在许多其他基因中也已鉴定出复发性启动子突变，并且在黑色素瘤中似乎尤为常见，但诸如对基因表达的影响等令人信服的功能数据却更难获得。在此，我们表明黑色素瘤中频繁出现的启动子突变几乎仅发生在由独特序列特征TTCCG侧翼的胞嘧啶处，端粒酶逆转录酶是一个显著的例外。在活跃而非不活跃的启动子中，基于紫外线三核苷酸突变特征，这种类ETS基序5'端胞嘧啶的突变频率远高于预期。进一步的分析证实了这种模式是一种扩展的上下文特异性突变特征，它介导了对紫外线诱变的特殊位置特异性易感性，这与正向选择相悖。我们进一步使用超灵敏扩增子测序来证明，暴露于紫外线的细胞培养物会迅速在受影响的位置特异性地产生亚克隆突变。我们的发现对调节区域体细胞突变的解释具有启示意义，并强调了基因组背景和扩展序列模式对于准确描述癌症突变特征的重要性。
