Abstract
Although aberrant N6-methyladenosine (m6A) RNA methylation has been linked to oncogenesis and tumor progression, the association between the deregulation of m6A regulators and invasive ductal carcinoma (IDC), the predominant subtype of breast cancer, remains unclear. In this study, we sought to determine the function of m6A RNA methylation regulators in IDC, with a particular focus on assessing their potential as prognostic biomarkers. To identify dysregulated m6A RNA methylation regulators, we systematically analyzed 656 samples from patients with IDC and 81 normal samples from The Cancer Genome Atlas (TCGA) database, and Cox univariate, LASSO-Cox regression, and stepwise regression analyses were conducted to construct a risk-prediction model for determining patient prognosis. Subsequently, we evaluated the prognostic value of the risk signature in IDC and assessed potential biological associations based on clinical survival analyses, examination of publicly available immunohistochemical staining data from the Human Protein Atlas, and two-sample Mendelian randomization. Among the IDC samples, we identified 12 m6A RNA methylation regulators characterized by significant dysregulation. Subsequently, a 4-gene signature comprising heterogeneous nuclear ribonucleoprotein C (HNRNPC), YTH domain-containing family proteins 2 and 3 (YTHDF2/3), and RNA-binding motif protein 15B (RBM15B) was constructed using machine learning algorithms. This signature was established to be an independent prognostic factor, particularly in patients with early stage IDC, and within the signature, HNRNPC was identified as a pivotal gene, the expression levels of which were demonstrated to be causally associated with the risk of IDC. On the basis of our findings in this study, we established a prognostic signature for IDC and identified a causal association between the expression of the signature gene HNRNPC and IDC risk. These findings indicate that m6A RNA methylation regulators could serve as molecular biomarkers for IDC and contribute to guiding therapeutic strategies.