A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies
A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies
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DOI：
10.1038/s41598-017-07888-0
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发表时间：
2017-08-09
影响因子：
4.6
通讯作者：
Nakamura, Jean L.
中科院分区：
文献类型：
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作者：
Davidson, Philip R.;Sherborne, Amy L.;Nakamura, Jean L.
在癌症基因组中发现的单核苷酸变异（snv）可以使用非负矩阵分解（NMF）将其解卷积成指示特定致癌过程的离散的基于三核苷酸的突变特征。nmf生成的突变签名的稳定性取决于可用于分析的变体的数量。在这项工作中，我们试图评估来自控制良好的小鼠模型的数据是否可以弥补某些癌症类型的稀缺人类数据。放疗诱导的癌症的高质量测序数据尤其缺乏，体内电离辐射（IR）诱导的突变过程定义不清。在这里，我们结合了来自ir诱导的恶性肿瘤小鼠模型和人类ir诱导的恶性肿瘤的测序数据。为了确定从暴露于ir的受试者中识别的特征是否可以与其他诱变特征区分开来，我们纳入了来自紫外线辐射（UV）诱导的人类皮肤癌和来自聚氨酯诱导的癌症小鼠模型的数据。NMF区分了所有三种诱变剂，在汇总分析中，IR与两种物种共有的突变特征相关。这些发现说明了对小鼠和人类测序数据进行汇总分析的实用性。
Single nucleotide variants (SNVs) identified in cancer genomes can be de-convolved using non-negative matrix factorization (NMF) into discrete trinucleotide-based mutational signatures indicative of specific cancer-causing processes. The stability of NMF-generated mutational signatures depends upon the numbers of variants available for analysis. In this work, we sought to assess whether data from wellcontrolled mouse models can compensate for scarce human data for some cancer types. High quality sequencing data from radiotherapy-induced cancers is particularly scarce and the mutational processes defining ionizing radiation (IR)-induced mutagenesis in vivo are poorly defined. Here, we combine sequencing data from mouse models of IR-induced malignancies and human IR-induced malignancies. To determine whether the signatures identified from IR-exposed subjects can be differentiated from other mutagenic signatures, we included data from an ultraviolet radiation (UV)-induced human skin cancer and from a mouse model of urethane-induced cancers. NMF distinguished all three mutagens and in the pooled analysis IR was associated with mutational signatures common to both species. These findings illustrate the utility of pooled analysis of mouse and human sequencing data.