Identification of Metastasis-Associated Genes in Triple-Negative Breast Cancer Using Weighted Gene Co-expression Network Analysis

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive and fatal sub-type of breast cancer. This study aimed to identify metastasis-associated genes that could serve as biomarkers for TNBC diagnosis and prognosis. RNA-seq data and clinical information on TNBC from the Cancer Genome Atlas were used to conduct analyses. Expression data were used to establish co-expression modules using average linkage hierarchical clustering. We used weighted gene co-expression network analysis to explore the associations between gene sets and clinical features and to identify metastasis-associated candidate biomarkers. The K-M plotter website was used to explore the association between the expression of candidate biomarkers and patient survival. In addition, receiver operating characteristic curve analysis was used to illustrate the diagnostic performance of candidate genes. The pale turquoise module was significantly associated with the occurrence of metastasis. In this module, 64 genes were identified, and its functional enrichment analysis revealed that they were mainly associated with transcriptional misregulation in cancer, microRNAs in cancer, and negative regulation of angiogenesis. Further, 4 genes, IGSF10, RUNX1T1, XIST, and TSHZ2, which were negatively associated with relapse-free survival and have seldom been reported before in TNBC, were selected. In addition, the mRNA expression levels of the 4 candidate genes were significantly lower in TNBC tumor tissues compared with healthy tissues. Based on the K-M plotter, these 4 genes were correlated with poor prognosis of TNBC. The area under the curve of IGSF10, RUNX1T1, TSHZ2, and XIST was 0.918, 0.957, 0.977, and 0.749. These findings provide new insight into TNBC metastasis. IGSF10, RUNX1T1, TSHZ2, and XIST could be used as candidate biomarkers for the diagnosis and prognosis of TNBC metastasis.

Integrated Bioinformatics Analysis for the Screening of Hub Genes and Therapeutic Drugs in Androgen Receptor-Positive TNBC

“…As a malignant disease whose pathogenesis is not fully understood, breast cancer is highly heterogeneous in terms of patient prognosis and tumor genetics. TNBC is more aggressive than other subtypes of BC, and patients suffering from TNBC showed a higher mortality rate [ 11 , 42 ]. The heterogeneous nature of TNBC makes the treatment of tumors more challenging.…”

“…Breast carcinoma is classified into four subtypes based on the expression of genes and receptor proteins [ 10 ]. TNBC accounts for 15-20% of all subtypes of BC and is usually described as ER-negative, PR-negative, or HER2-negative [ 11 ]. In 2011, Lehmann et al performed a cluster analysis on the gene expression profiles of 587 patients with TNBC from 21 public databases and proposed that TNBC could be divided into 6 subtypes based on the gene expression level.…”

Integrative multiomics analysis identifies a metastasis-related gene signature and the potential oncogenic role of EZR in breast cancer

“…Compared with previous studies [11,39], we constructed a nine-MRG prognostic signature using TCGA-BRCA datasets and validated its accuracy in TCGA, METABRIC, and GEO datasets. This application of multiple platform datasets ensures the applicability of the risk model.…”

Molecular Mechanisms of Breast Cancer Metastasis

“…It was also known to have a relationship with cancer cases since its expression was observed to be dysregulated in some cases. TSHZ2 is a member of the TSHZ family and like the others, its expression was observed in other cancer types and was found to have a downregulation in some cancers [90].…”

“…In a study, 26 hub genes were identified as metastasis-associated candidate genes [90]. In-depth studies with four of them, Immunoglobulin Superfamily Member 10 (IGSF10), Runt-related transcription factor 1 translocation partner 1 (RUNX1T1), X-inactive specific transcript (XIST), and transcription factor teeshirt zinc finger homeobox 2 (TSHZ2) indicated that they were downregulated in TNBC tissues and these genes have prognostic and diagnosis values in TNBC [90]. IGSF10 is an immunoglobulin superfamily member 10 normally associated with developmental processes and differentiation [91].…”