Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer.
Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer.
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综合转录组分析鉴定出三阴性乳腺癌的新分子亚型和亚型特异性 RNA
DOI：
10.1186/s13058-016-0690-8
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Shao ZM
中科院分区：
文献类型：
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作者：
Liu YR;Jiang YZ;Xu XE;Yu KD;Jin X;Hu X;Zuo WJ;Hao S;Wu J;Liu GY;Di GH;Li DQ;He XH;Hu WG;Shao ZM
背景三阴性乳腺癌(TNBC)是一组高度异质性的肿瘤，为了更好地识别基于分子的治疗方法，分子亚型是必要的。虽然已经建立了一些分类器，但还没有人将长非编码RNA(LncRNAs)的表达谱整合到这样的亚型标准中。考虑到lncRNAs在细胞过程中的重要作用，结合信使RNA和lncRNA的转录组图谱的新分类将有助于我们更好地了解TNBC的异质性。方法利用人转录组芯片，分析165例TNBC样本的转录组图谱。我们使用k-均值聚类法和经验累积分布函数来确定最优的TNBC亚型数量。基因本体论(GO)和通径分析用于确定亚型特异性基因和通路的主要功能。结果165例TNBC肿瘤可分为免疫调节亚型(IM)、管腔雄激素受体亚型(LAR)、间充质样亚型(MES)和基底细胞样免疫抑制亚型(BLIS)。IM亚型高表达免疫细胞信号和细胞因子信号基因。LAR亚型以雄激素受体信号为特征。生长因子信号通路丰富了MES亚型。BLIS亚型以免疫反应基因下调、细胞周期激活和DNA修复为特征。这一亚型患者的无复发生存率比其他亚型患者差(LOG RANK检验，P= 0.045)。结论我们建立了一个新的TNBC分类系统，整合了mRNAs和lncRNAs的表达谱，确定了具有潜在生物标志物和靶点的亚型特异性lncRNAs。如果在更大的人群中进一步验证，我们的新分类系统将有助于患者咨询和TNBC的个体化治疗。
BackgroundTriple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular-based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC.MethodsUsing human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs.ResultsAll of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test,P= 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses.ConclusionsWe developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC.