N6-methyladenosine-related genes contribute to malignant progression, have clinical prognostic and neoadjuvant treatments response impact for breast cancer

Abstract

N6-methyladenosine (m6A) methylation dysregulation contributes to tumorigenesis and breast cancer development. This study intends to conduct a comprehensive analysis for determining the clinical significance of m6A-related genes and establishing m6A-related gene-based risk signature to predict the clinical outcomes and neoadjuvant treatments response for breast cancer patients. The m6Avar database was utilized for downloading the m6A-regulated genes. The Cancer Genome Atlas (TCGA) database was utilized for downloading breast cancer patients’ RNA-Seq data and clinicopathological information. For determining the differentially expressed m6A-related gene, a one-way analysis of variance (ANOVA) was conducted. The interaction and correlation of m6A-related genes were evaluated using search tool for the retrieval of interacting genes/proteins (STRING) and Spearmen test. For determining clusters of breast cancer patients with different clinical outcomes, a consensus clustering analysis was conducted. We screened differentially expressed genes and functional enrichment pathways between subgroups utilizing gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG). We constructed and verified a prognostic signature utilizing Cox regression analysis as well as a least absolute shrinkage and selection operator (LASSO) regression model. 286 genes were detected as significantly differentially expressed in different stages, including 3 m6A RNA methylation regulators, Wilms tumor 1-associating protein (WTAP), YT521-B homology (YTH) domain containing 2 (YTHDC2), and YTH domain family 2 (YTHDF2). A 13-gene prognostic signature was constructed and could predict the overall survival and the neoadjuvant treatments response in breast cancer patients. We categorized breast cancer patients into four groups based on m6A-associated RNAs expression. Significant differences were found in the overall survivals among the four clusters of patients. The biological processes and the key signaling pathways closely related to breast cancer have a close connection to the four clusters. This study confirmed that the m6A-related genes expression levels were highly associated with prognosis and neoadjuvant treatment response in breast cancer and constructed an effective m6A-related gene-based risk signature for predicting the prognosis of patients with breast cancer.