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Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.
International Journal of Genomics ( IF 2.9 ) Pub Date : 2020-07-07 , DOI: 10.1155/2020/2641370
Jiande Wu 1 , Tarun K K Mamidi 2 , Lu Zhang 3 , Chindo Hicks 1
Affiliation  

Background. Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer. Methods. We addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations. Results. The investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC. Conclusions. The results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.

中文翻译:

三阴性和非三阴性乳腺癌的种系和体细胞突变相互作用景观的描绘。

背景。乳腺癌的发展和进展涉及种系和体细胞突变。高通量基因分型和下一代测序技术使人们能够发现遗传风险变异和驱动疾病的获得性体细胞突变。然而,种系遗传风险变异与三阴性乳腺癌(TNBC)和非三阴性乳腺癌(非TNBC)中体细胞突变之间可能的致癌相互作用尚未得到表征。在这里,我们描述了 TNBC 和非 TNBC 中含有种系和体细胞突变的基因之间可能的致癌相互作用,并研究了两种类型的乳腺癌之间的基因表达和突变负担是否存在差异。方法. 我们通过使用基因表达数据作为中间表型将来自全基因组关联研究的种系突变信息与来自下一代测序的体细胞突变信息整合来解决这个问题。我们进行了网络和通路分析,以发现富含种系和体细胞突变的分子网络和信号通路。结果. 调查揭示了 TNBC 和非 TNBC 之间差异表达和差异体细胞突变基因的特征。网络和通路分析揭示了在基因调控网络中相互作用的功能相关基因和多种信号通路,这些通路富含每种乳腺癌的种系和体细胞突变。发现的信号通路包括 TNBC 的 DNA 修复和雄激素和 ATM 信号通路,以及非 TNBC 的 DNA 损伤反应、癌症的分子机制和 ATM 和 GP6 信号通路。结论. 结果表明,整合基因组学是描述 TNBC 和非 TNBC 中含有种系的基因与含有体细胞突变的基因之间的致癌相互作用的有力方法,并在遗传和体细胞改变以及它们在两种类型的乳房中控制的途径之间建立了假定的功能桥梁癌症。
更新日期:2020-07-07
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