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. 2022 Oct 11:13:990143.
doi: 10.3389/fimmu.2022.990143. eCollection 2022.

Identifying enhancer-driven subtype-specific prognostic markers in breast cancer based on multi-omics data

Hongying Zhao  1 , Siwen Zhang  1 , Xiangzhe Yin  1 , Caiyu Zhang  1 , Lixia Wang  1 , Kailai Liu  1 , Haotian Xu  1 , Wangyang Liu  1 , Lin Bo  1 , Shihua Lin  1 , Ke Feng  1 , Lin Lin  1 , Meiting Fei  1 , Shangwei Ning  1 , Li Wang  1
Affiliations

Identifying enhancer-driven subtype-specific prognostic markers in breast cancer based on multi-omics data

Hongying Zhao et al. Front Immunol. .

Abstract

Breast cancer is a cancer of high complexity and heterogeneity, with differences in prognosis and survival among patients of different subtypes. Copy number variations (CNVs) within enhancers are crucial drivers of tumorigenesis by influencing expression of their targets. In this study, we performed an integrative approach to identify CNA-driven enhancers and their effect on expression of target genes in four breast cancer subtypes by integrating expression data, copy number data and H3K27ac data. We identified 672, 555, 531, 361 CNA-driven enhancer-gene pairs and 280, 189, 113 and 98 CNA-driven enhancer-lncRNA pairs in the Basal-like, Her2, LumA and LumB subtypes, respectively. We then reconstructed a CNV-driven enhancer-lncRNA-mRNA regulatory network in each subtype. Functional analysis showed CNA-driven enhancers play an important role in the progression of breast cancer subtypes by influencing P53 signaling pathway, PPAR signaling pathway, systemic lupus erythematosus and MAPK signaling pathway in the Basal-like, Her2, LumA and LumB subtypes, respectively. We characterized the potentially prognostic value of target genes of CNV-driven enhancer and lncRNA-mRNA pairs in the subtype-specific network. We identified MUM1 and AC016876.1 as prognostic biomarkers in LumA and Basal-like subtypes, respectively. Higher expression of MUM1 with an amplified enhancer exhibited poorer prognosis in LumA patients. Lower expression of AC016876.1 with a deleted enhancer exhibited poorer survival outcomes of Basal-like patients. We also identified enhancer-related lncRNA-mRNA pairs as prognostic biomarkers, including AC012313.2-MUM1 in the LumA, AC026471.4-PLK5 in the LumB, AC027307.2-OAZ1 in the Basal-like and AC022431.1-HCN2 in the Her2 subtypes. Finally, our results highlighted target genes of CNA-driven enhancers and enhancer-related lncRNA-mRNA pairs could act as prognostic markers and potential therapeutic targets in breast cancer subtypes.

Keywords: breast cancer subtype; copy number variation; enhancer; lncRNA; prognostic marker.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Identification of copy number variation-driven enhancers in breast cancer. (A) The analysis of copy number variation in breast cancer by GISTIC2.0. The left panel shows CNV variation heatmap, the middle panel shows copy number amplification regions and the right panel shows copy number deletion regions. (B) Waterfall plot of CNV rates in breast cancer. The red line indicates copy number amplification and the blue line indicates copy number deletion. (C) Chromosomal distribution of copy number variation-driven enhancers. (D) Comparative analysis of significant copy number variation regions in four subtypes of breast cancer. The left panel shows illustrates the variation of the significant CNV region in four subtypes and the overall mutation rate of these CNV region. The right panel shows a heatmap of folds of CNV mutation rate of each subtypes and total mutation rate.
Figure 2
Figure 2
The effect of CNA-driven enhancers on expression of target genes. Venn diagram of differential genes (A) and differential lncRNAs (B) in the four subtypes. (C) Differential gene expression profiles of the four subtypes, and the differential gene set is the sum of the four subtype-specific differential gene sets. (D) Differential lncRNA expression profiles of the four subtypes, and the differential lncRNA set is the sum of the four subtype-specific differential lncRNA sets. (E) The top-ranked terms of GO function and KEGG pathway for differentially expressed genes in Basal-like, her2, LumA and LumB subtypes using DAVID.
Figure 3
Figure 3
The relationship between CNV-driven enhancer target genes and related lncRNAs (A) Venn diagram analysis of CNV-driven enhancer target genes and related lncRNAs of four subtypes of breast cancer. The top panel shows the CNV-driven enhancer target genes and related lncRNAs, respectively, in the four subtypes. The bottom panel shows the enhancers of DEGs and the enhancers of DELs in the four subtypes. (B) Correlation analysis of differentially expressed genes and differentially expressed lncRNAs in four subtypes of breast cancer. X-axis is symbol of DEGs and y-axis is symbol of DELs. (C) Copy number variation of enhancers (chr16:2239402-2252300; chr16:1771890-1773150; chr16:2268155-2273418) and expression levels of ECI1, MRPS34 and AC009065.4 in breast cancer samples.
Figure 4
Figure 4
The CNV-driven enhancer-lncRNA-mRNA networks in Basal-like subtype (A), Her2 subtype (B), LumA subtype (C) and LumB subtype (D). The diamond represents CNA-driven enhancers (red: amplification; blue: deletion). The circle and square indicate differentially expressed genes and lncRNAs, respectively. Pink denotes upregulation and green denotes downregulation.
Figure 5
Figure 5
Functional enrichment analysis of target genes of CNA-driven enhancers in breast cancer subtypes. (A) Copy number variation of enhancers (chr19:1285886-1286032; chr19:1267471-1270260) and expression levels of MUM1 and CIRBP-AS1 in breast cancer samples. (B) Copy number variation of enhancers (chr17:7484011-7484247; chr17:1650629-1684867) and expression levels of AC016876.1 and PRPF8 in breast cancer samples. (C) Copy number variation of enhancers (chr16:84144692-84145136; chr16:84116444-84116897) and expression levels of MBTPS1 and AC040169.1 in breast cancer samples. (D) GO function and KEGG pathway analysis for key genes in the CNA-driven enhancer-lncRNA-mRNA network in Basal-like, her2, LumA and LumB subtypes of breast cancer using DAVID. The significance threshold was FDR less than 0.05.
Figure 6
Figure 6
Target genes of CNA-driven enhancers elements and lncRNA-mRNA pairs are associated with prognosis in breast cancer subtypes. (A) Kaplan-Meier survival curves according to the gene expression or risk score of lncRNA-mRNA in breast cancer subtypes. The log-rank test was used to estimate the difference in survival time. (B) The differential expression of prognostic markers across the four subtypes using one-way ANOVA. (*p < 0.05). (C) Copy number variation of enhancers (chr19:589881-617159; chr19:1508023-1536046) and expression levels of HCN2, PLK5 and their co-expressed genes in breast cancer samples.
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