The analysis of tumour genome sequences has demonstrated high rates of base substitution mutagenesis upon the inactivation of DNA mismatch repair (MMR), and the resulting somatic mutations in MMR deficient tumours appear to significantly enhance the response to immune therapy. A handful of different algorithmically derived base substitution mutation signatures have been attributed to MMR deficiency in tumour somatic mutation datasets. In contrast, mutation data obtained from whole genome sequences of isogenic wild type and MMR deficient cell lines in this study, as well as from published sources, show a more uniform experimental mutation spectrum of MMR deficiency. In order to resolve this discrepancy, we reanalysed mutation data from MMR deficient tumour whole exome and whole genome sequences. We derived two base substitution signatures using non-negative matrix factorisation, which together adequately describe mutagenesis in all tumour and cell line samples. The two new signatures broadly resemble COSMIC signatures 6 and 20, but perform better than existing COSMIC signatures at identifying MMR deficient tumours in mutation signature deconstruction. We show that the contribution of the two identified signatures, one of which is dominated by C to T mutations at CpG sites, is biased by the different sequence composition of the exome and the whole genome. We further show that the identity of the inactivated MMR gene, the tissue type, the mutational burden or the patient's age does not influence the mutation spectrum, but that a tendency for a greater contribution by the CpG mutational process is observed in tumours as compared to cultured cells. Our analysis suggest that two separable mutational processes operate in the genomes of MMR deficient cells.

中文翻译：

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在没有DNA错配修复的情况下，有两个主要的突变过程。

肿瘤基因组序列的分析表明，DNA错配修复（MMR）失活后，碱基取代诱变的发生率很高，而MMR缺陷型肿瘤中的体细胞突变似乎显着增强了对免疫疗法的反应。几种不同的算法得出的碱基取代突变签名已归因于肿瘤体细胞突变数据集中的MMR缺乏。相反，从这项研究的等基因野生型和MMR缺陷细胞系的全基因组序列以及从公开的来源获得的突变数据显示MMR缺陷的实验突变谱更加统一。为了解决这种差异，我们重新分析了MMR缺陷的肿瘤全外显子组和全基因组序列的突变数据。我们使用非负矩阵分解法得出了两个碱基取代标记，它们一起充分描述了所有肿瘤和细胞系样品中的诱变作用。这两个新签名在很大程度上类似于COSMIC签名6和20，但在鉴定突变签名解构中的MMR缺陷型肿瘤时，其性能优于现有的COSMIC签名。我们表明，两个已识别特征的贡献（其中一个受CpG位点的C到T突变支配）受外显子组和整个基因组的不同序列组成所影响。我们进一步证明灭活的MMR基因的身份，组织类型，突变负担或患者年龄不会影响突变谱，但是与培养细胞相比，在肿瘤中观察到CpG突变过程有更大贡献的趋势。我们的分析表明，MMR缺陷细胞的基因组中有两个可分离的突变过程。