Comprehensive molecular biomarker identification in breast cancer brain metastases.
Comprehensive molecular biomarker identification in breast cancer brain metastases.
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DOI：
10.1186/s12967-017-1370-x
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发表时间：
2017-12-29
影响因子：
7.4
通讯作者：
Al-Qahtani MH
中科院分区：
文献类型：
--
作者：
Schulten HJ;Bangash M;Karim S;Dallol A;Hussein D;Merdad A;Al-Thoubaity FK;Al-Maghrabi J;Jamal A;Al-Ghamdi F;Choudhry H;Baeesa SS;Chaudhary AG;Al-Qahtani MH
乳腺癌脑转移（BCBM）发生在约20-30%的乳腺癌（BC）患者中。BCBM与预后不良相关，至少是因为缺乏有价值的分子治疗靶点。该研究的目的是通过使用互补的最先进的技术来鉴定BCBM中的新分子生物标志物和靶点。我们比较了16例非脑转移性BC和16例原发性脑肿瘤（prBT）的3种BCBM的阵列表达谱，采用假发现率（FDR） p < 0.05和折叠变化（FC） bbb2。对差异表达的探针集进行生物功能分析。采用高密度阵列检测拷贝数变异（CNVs），采用末端配对长度为150 bp的全外显子组测序（WES）检测3个BCBM的基因突变。BCBM与BC和prBT之间差异表达最多的370个探针集，在BCBM中大部分是相对过表达的，包括编码基因BCL3、BNIP3、BNIP3P1、BRIP1、CASP14、CDC25A、DMBT1、IDH2、E2F1、MYCN、RAD51、RAD54L和VDR。许多小核核rna （snoRNAs）在BCBM中均有过表达，包括SNORA1、SNORA2A、SNORA9、SNORA10、SNORA22、SNORA24、SNORA30、SNORA37、SNORA38、SNORA52、SNORA71A、SNORA71B、SNORA71C、SNORD13P2、SNORD15A、SNORD34、SNORD35A、SNORD41、SNORD53和SCARNA22。最典型的途径是BRCA1在DNA损伤反应中的作用。网络分析显示Akt、ERK1/2、NFkB和Ras是预测激活阶段的关键节点。BCBM和prBT共享的数据集中下调的基因包括：BC细胞系侵袭标记JUN、MMP3、TFF1和HAS2。受CNVs影响的重要癌症基因包括TP53、BRCA1、BRCA2、ERBB2、IDH1和IDH2。WES检测到许多突变，其中一些影响BC相关基因，如CDH1、HEPACAM和LOXHD1。利用互补的分子遗传学技术，本研究确定了三种高度异常的BCBM的共享和非共享分子事件，强调了检测具有翻译意义的新分子生物标志物和靶点的挑战。有能力获得临床相关性的新发现是检测过度表达的snoRNAs，已知其调节一些关键的细胞功能，如核糖体生物发生。本文的在线版本（10.1186/s12967-017-1370-x）包含补充材料，可供授权用户使用。
Breast cancer brain metastases (BCBM) develop in about 20–30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques. We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM. The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3, BNIP3, BNIP3P1, BRIP1, CASP14, CDC25A, DMBT1, IDH2, E2F1, MYCN, RAD51, RAD54L, and VDR. A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1, SNORA2A, SNORA9, SNORA10, SNORA22, SNORA24, SNORA30, SNORA37, SNORA38, SNORA52, SNORA71A, SNORA71B, SNORA71C, SNORD13P2, SNORD15A, SNORD34, SNORD35A, SNORD41, SNORD53, and SCARNA22. The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53, BRCA1, BRCA2, ERBB2, IDH1, and IDH2. WES detected numerous mutations, some of which affecting BC associated genes as CDH1, HEPACAM, and LOXHD1. Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis. The online version of this article (10.1186/s12967-017-1370-x) contains supplementary material, which is available to authorized users.
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