Huang Teng, Li Jiaheng, Wang San Ming
Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR 999078, China.
Genes Dis. 2022 Feb 24;10(1):228-238. doi: 10.1016/j.gendis.2022.01.003. eCollection 2023 Jan.
Abnormal gene expression plays key role in cancer development. A core promoter is located around the transcriptional start site. Through interaction between core promoter sequences and transcriptional factors, core promoter controls transcriptional initiation. We hypothesized that in cancer, core promoter sequences could be mutated to interfere the interaction with transcriptional factors, resulting in altered transcriptional initiation and abnormal gene expression and cancer development. We used triple-negative breast cancer (TNBC) as a model to test our hypothesis. We collected genome-wide core promoter variants from 279 TNBC genomes. After extensive filtering of normal genomic polymorphism, we identified 19,427 recurrent somatic variants in 1,238 core promoters of 1,274 genes and 1,694 recurrent germline variants in 272 core promoters of 294 genes. Many of the affected genes were oncogenes and tumor suppressors. Analysis of RNA-seq data from the same patient cohort identified increased or decreased gene expression in 439 somatic and 85 germline variants-affected genes, and the results were validated by luciferase reporter assay. By comparing with the core promoter variation data from 610 unclassified breast cancer, we observed that core promoter variants in TNBC were highly TNBC-specific. We further identified the drugs targeting the genes with core promoter variation. Our study demonstrates that core promoter is highly mutable in cancer, and can play etiological roles in TNBC and other types of cancer through influencing transcriptional initiation.
异常基因表达在癌症发展中起关键作用。核心启动子位于转录起始位点周围。通过核心启动子序列与转录因子之间的相互作用，核心启动子控制转录起始。我们假设在癌症中，核心启动子序列可能发生突变，从而干扰与转录因子的相互作用，导致转录起始改变、基因表达异常以及癌症发展。我们以三阴性乳腺癌（TNBC）为模型来验证我们的假设。我们从279个TNBC基因组中收集了全基因组范围的核心启动子变异。在对正常基因组多态性进行广泛筛选后，我们在1274个基因的1238个核心启动子中鉴定出19427个复发性体细胞变异，在294个基因的272个核心启动子中鉴定出1694个复发性种系变异。许多受影响的基因是癌基因和肿瘤抑制基因。对来自同一患者队列的RNA-seq数据的分析确定了439个体细胞变异和85个种系变异影响的基因中基因表达的增加或减少，并且结果通过荧光素酶报告基因测定得到验证。通过与610例未分类乳腺癌的核心启动子变异数据进行比较，我们观察到TNBC中的核心启动子变异具有高度的TNBC特异性。我们进一步鉴定了针对具有核心启动子变异的基因的药物。我们的研究表明，核心启动子在癌症中高度可变，并且可以通过影响转录起始在TNBC和其他类型的癌症中发挥病因学作用。
