Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks

The identification of functional non-coding mutations is a key challenge in the field of genomics. Here we introduce μ-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying ‘personal’ gene regulatory network. We validated μ-cisTarget by re-analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genome of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers.EGA study EGAS00001002571

在基因组学领域，鉴定具有功能效应的非编码突变是一项核心研究挑战。本研究推出μ-cisTarget工具，可基于突变对目标‘个性化’基因调控网络的潜在效应，对顺式调控突变进行筛选、注释与优先级排序。我们通过重新分析T细胞急性淋巴细胞白血病（T-ALL）中的TAL1与LMO1增强子突变，以及黑色素瘤中的端粒酶逆转录酶（TERT）启动子突变，对μ-cisTarget的有效性进行了验证。随后，我们对10株癌细胞系的全基因组开展重测序，并结合匹配的转录组数据与基序发现分析，鉴定出携带新生结合位点的主调控因子，此类结合位点可促使邻近致癌驱动基因的表达上调。本研究关联的EGA研究编号为EGAS00001002571。