Race Disparities in the Contribution of miRNA Isoforms and tRNA-Derived Fragments to Triple-Negative Breast Cancer.
Race Disparities in the Contribution of miRNA Isoforms and tRNA-Derived Fragments to Triple-Negative Breast Cancer.
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DOI：
10.1158/0008-5472.can-17-1947
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发表时间：
2018-03-01
期刊：
影响因子：
11.2
通讯作者：
Rigoutsos I
中科院分区：
文献类型：
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作者：
Telonis AG;Rigoutsos I
三阴性乳腺癌(TNBC)是一种以白人和黑人/非裔美国女性之间明显差异为特征的乳腺癌亚型。我们对来自癌症基因组图谱(TCGA)的数据集进行了系统水平的分析，以阐明调控非编码RNA(NcRNAs)是如何塑造信使RNA(MRNAs)的表达模式的。具体地说，我们研究了异构体，即microRNAs的异构体(MiRNAs)和tRNA衍生片段(TRFs)。在正常乳腺组织中，我们观察到ncRNA和mRNA层的显著凝聚性以及它们之间的联系。这种凝聚力在TNBC中被广泛破坏：许多mRNAs在正常乳腺和TNBC之间变得差异表达或差异连接，伴随着isomiR或TRF失调。受影响的途径包括能量代谢、细胞信号和免疫反应。在TNBC中，受影响的通路与异构体和TRFs的连接在每个种族中都不同。来自特定miRNA基因座(例如miR-200C、miR-21、miR-17/92簇、miR-183/96/182簇)和特定tRNA基因座(例如核tRNAGly和tRNALeu、线粒体tRNAVal和tRNAPro)的多个异构体和TRF与观察到的TNBC种族差异密切相关。我们通过详细讨论与转移相关的MAPK和Wnt/β-catenin信号通路来强调转录组连接的种族特异性方面，这是许多发现差异连接的关键通路中的两个。总之，通过采用数据和知识驱动的方法，我们全面分析了正常和癌症转录本，以揭示基于种族的TNBC差异的新的关键因素。
Triple-Negative Breast Cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas (TCGA) to elucidate how the expression patterns of messenger RNAs (mRNAs) are shaped by regulatory non-coding RNAs (ncRNAs). Specifically, we studied isomiRs, i.e. isoforms of microRNAs (miRNAs), and tRNA-derived fragments (tRFs). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC: many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g. the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race-specific aspects of transcriptome wiring by discussing in detail the metastasis-related MAPK and the Wnt/β-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data- and knowledge-driven approach we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC.