MicroRNAs (miRNAs) play critical roles in cancer initiation and progression, which were critical components to maintain the dynamic balance of competing endogenous RNA (ceRNA) networks. Somatic copy number alterations (SCNAs) in the cancer genome could disturb the transcriptome level of miRNA to deregulate this balance. However, the driving effects of SCNAs of miRNAs were insufficiently understood. In this study, we proposed a method to dissect the functional roles of miRNAs under different copy number states and identify driver miRNAs by integrating miRNA SCNAs profile, miRNA-target relationships and expression profiles of miRNA, mRNA and lncRNA. Applying our method to 813 TCGA breast cancer (BRCA) samples, we identified 29 driver miRNAs whose SCNAs significantly and concordantly regulated their own expression levels and further inversely dysregulated expression levels of their targets or disturbed the miRNA-target networks they directly involved. Based on miRNA-target networks, we further constructed dynamic ceRNA networks driven by driver SCNAs of miRNAs and identified three different patterns of SCNA interference in the miRNA-mediated dynamic ceRNA networks. Survival analysis of driver miRNAs showed that high-level amplifications of four driver miRNAs (including has-miR-30d-3p, has-mir-30b-5p, has-miR-30d-5p and has-miR-151a-3p) in 8q24 characterized a new BRCA subtype with poor prognosis and contributed to the dysfunction of cancer-associated hallmarks in a complementary way. The SCNAs of driver miRNAs across different cancer types contributed to the cancer development by dysregulating different components of the same cancer hallmarks, suggesting the cancer specificity of driver miRNA. These results demonstrate the efficacy of our method in identifying driver miRNAs and elucidating their functional roles driven by endogenous SCNAs, which is useful for interpreting cancer genomes and pathogenic mechanisms.

中文翻译：

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识别具有体细胞拷贝数改变的驱动 miRNA，驱动癌症中 ceRNA 网络失调

MicroRNA (miRNA) 在癌症发生和进展中发挥着关键作用，是维持竞争性内源性 RNA (ceRNA) 网络动态平衡的关键组成部分。癌症基因组中的体细胞拷贝数改变 (SCNA) 可能会扰乱 miRNA 的转录组水平，从而打破这种平衡。然而，SCNA 对 miRNA 的驱动作用尚不清楚。在本研究中，我们提出了一种方法，通过整合miRNA SCNA谱、miRNA-靶标关系以及miRNA、mRNA和lncRNA的表达谱来剖析miRNA在不同拷贝数状态下的功能作用并识别驱动miRNA。将我们的方法应用于 813 个 TCGA 乳腺癌 (BRCA) 样本，我们鉴定了 29 个驱动 miRNA，其 SCNA 显着且一致地调节其自身的表达水平，并进一步反向失调其靶标的表达水平或扰乱它们直接参与的 miRNA 靶标网络。基于miRNA目标网络，我们进一步构建了由miRNA驱动SCNA驱动的动态ceRNA网络，并确定了miRNA介导的动态ceRNA网络中三种不同的SCNA干扰模式。驱动 miRNA 的生存分析表明，四种驱动 miRNA（包括 has-miR-30d-3p、has-mir-30b-5p、has-miR-30d-5p 和 has-miR-151a-3p）在8q24 表征了一种预后不良的新 BRCA 亚型，并以互补的方式导致癌症相关标志的功能障碍。不同癌症类型的驱动 miRNA 的 SCNA 通过失调相同癌症标志的不同成分来促进癌症的发展，这表明驱动 miRNA 的癌症特异性。这些结果证明了我们的方法在识别驱动 miRNA 并阐明其由内源 SCNA 驱动的功能作用方面的有效性，这对于解释癌症基因组和致病机制非常有用。