Effect of N6-Methyladenosine Regulators on Progression and Prognosis of Triple-Negative Breast Cancer
Abstract
Background: The N6-methyladenosine (m6A) modification plays a pivotal role in cancer progression, yet its involvement in triple-negative breast cancer (TNBC)—the most aggressive form of breast cancer—remains poorly understood. Therefore, the prognostic value of m6A RNA methylation in TNBC warrants further investigation.
Methods: We compared the expression levels of 13 m6A methylation regulators between 98 TNBC tumor samples and corresponding normal tissue samples using transcriptome data from The Cancer Genome Atlas (TCGA). The relationship between m6A regulators and patient overall survival was analyzed through Kaplan-Meier survival analysis and Cox regression analysis. To develop a prognostic model based on the m6A methylation system, we applied Lasso regression analysis. The performance of the model was validated using the GSE88847 and GSE135565 datasets. Additionally, we constructed a nomogram combining the TNM stage with the m6A prognostic model for improved survival prediction in TNBC patients.
Results: The expression of m6A regulator genes was significantly altered in TNBC tumor tissues. Specifically, ALKBH5, YTHDF2, HNRNPC, KIAA1429, and RBM15 were notably upregulated, while FTO, YTHDC1, YTHDC2, METTL3, METTL14, and ZC3H13 were significantly downregulated (P < 0.01). ALKBH5 expression emerged as an independent unfavorable prognostic factor (HR = 3.327, P = 0.006), whereas METTL14 was identified as an independent favorable prognostic factor (HR = 0.425, P = 0.009) for TNBC patients. A prognostic model integrating ALKBH5 and METTL14 demonstrated enhanced risk prediction accuracy when combined with TNM stage, yielding an AUC of 0.791. The prognostic value of this signature was consistently validated in two external datasets. Conclusion: m6A methylation regulators are significantly dysregulated in TNBC DDO-2728 tissues and could serve as a novel prognostic signature to predict survival outcomes in TNBC patients.