Abstract
Breast cancer (BRCA) is the most leading cause of cancer worldwide. It is a heterogeneous disease with at least five molecular subtypes including luminal A, luminal B, basal-like, HER2-enriched, and normal-like. These five molecular subtypes are usually stratified according to their mRNA profile patterns; however, ncRNAs are increasingly being used for this purpose. Among the ncRNAs class, the long non-coding RNAs (lncRNAs) are molecules with more than 200 nucleotides with versatile regulatory roles; and high tissue-specific expression profiles. The heterogeneity of BRCA can also be reflected regarding tumor microenvironment immune cells composition, which can directly impact a patient’s prognosis and therapy response. Using BRCA immunogenomics data from a previous study, we propose here a bioinformatics approach to include lncRNAs complexity in BRCA molecular and immune subtype. RNA-seq data from The Cancer Genome Atlas (TCGA) BRCA cohort was analyzed, and signal-to-noise ratio metrics were applied to create these subtype-specific signatures. Five immune-related signatures were generated with approximately ten specific lncRNAs, which were then functionally analyzed using GSEA enrichment and survival analysis. We highlighted here some lncRNAs in each subtype. LINC01871 is related to immune response activation and favorable overall survival in basal-like samples; EBLN3P is related to immune response suppression and progression in luminal B, MEG3, XXYLT1-AS2, and LINC02613 were related with immune response activation in luminal A, HER2-enriched and normal-like subtypes, respectively. In this way, we emphasize the need to know better the role of lncRNAs as regulators of immune response to provide new perspectives regarding diagnosis, prognosis and therapeutical targets in BRCA molecular subtypes.
Highlights
Breast cancer (BRCA) is a molecular and histological heterogeneous disease with at least five intrinsic molecular subtypes [1, 2]
Based on the gene expression profile related to immune response, Throsson et al [8] analyzed over 10,000 The Cancer Genome Atlas (TCGA) samples, from which 1,087 were from BRCA samples and clustered them in six immune subtypes
After selecting the 0.98 quantile (Figure 2B and Supplementary Table 3), 11 long non-coding RNAs (lncRNAs) remained, of which only one was shared between Her2 and Basal, the lncRNA KLHDC7B-DT (ENSG00000272666). This lncRNA was removed for further analysis as we looked for a specific lncRNA signature related to each BRCA molecular subgroup
Summary
Breast cancer (BRCA) is a molecular and histological heterogeneous disease with at least five intrinsic molecular subtypes [1, 2]. BRCA can be mainly classified into luminal A (LumA), luminal B (LumB), HER2-enriched (Her2), basal-like (Basal), and normal-like (Normal) [3, 4]. These subtypes have a distinct prognosis and differ according to therapeutic. Besides gene expression differences in BRCA molecular subtypes, they differ significantly concerning the composition of cells that form the tumor microenvironment, especially the immune system’s cells. A substantial proportion of natural killer cells and neutrophils have been found in luminal tumors. In BRCA Basal tumors, T regs, associated macrophages 2, and activated mast cells form a significant portion of the immune infiltrate cells. It is known that it is mainly formed by dendritic cells, mast cells, gd T lymphocytes, T regs and neutrophils [9]
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