Abstract
Background: The N6-methyladenosine (m6A) modification plays a critical role in cancer development. Little is known about the m6A modification in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Thus, the prognostic value of m6A RNA methylation in TNBC deserves exploration.Methods: The expression levels of the 13 m6A methylation regulators were compared between the 98 TNBC tumor samples and normal tissue samples based on the transcriptome profiles from The Cancer Genome Atlas (TCGA). The association between the m6A regulators and patients' overall survival was assessed by Kaplan-Meier survival analysis and Cox regression analysis. Lasso regression analysis was conducted to construct a prognostic model based on the m6A methylation system. The prognostic performance of the identified model was validated in GSE88847 and GSE135565 datasets. A nomogram combining the TNM stage and the m6A prognostic model was further constructed for the survival prediction of TNBC patients.Results: The m6A regulator genes were remarkably dysregulated in TNBC tumor tissues, with ALKBH5, YTHDF2, HNRNPC, KIAA1429, and RBM15 significantly up-regulated and FTO, YTHDC1, YTHDC2, METTL3, METTL14, and ZC3H13 significantly down-regulated (P < 0.01). The expression level of ALKBH5 was an independent unfavorable prognostic factor (HR = 3.327, P = 0.006), while METTL14 (HR = 0.425, P = 0.009) was an independent favorable prognostic factor for TNBC patients. A prognostic model consisting of ALKBH5 and METTL14 was therefore proposed displaying higher accuracy of risk prediction when combined with TNM stage with an AUC of 0.791. The prognostic value of the identified signature remained consistent within the two external validation datasets.Conclusion: The m6A methylation regulators were significantly dysregulated in TNBC tissues and could constitute a novel prognostic signature for the survival prediction of TNBC patients.
Highlights
Breast cancer (BC) is one of the most life-threatening malignancies in females
The m6A regulator genes were remarkably dysregulated in triple-negative breast cancer (TNBC) tumor tissues, with ALKBH5, YTHDF2, HNRNPC, KIAA1429, and RBM15 significantly upregulated and FTO, YTHDC1, YTHDC2, METTL3, METTL14, and ZC3H13 significantly down-regulated (P < 0.01)
A prognostic model consisting of ALKBH5 and METTL14 was proposed displaying higher accuracy of risk prediction when combined with TNM stage with an AUC of 0.791
Summary
Breast cancer (BC) is one of the most life-threatening malignancies in females. Since triple-negative breast cancer (TNBC) tends to behave more aggressively and has a relatively worse prognosis than the other subtypes, the appropriate prognostic prediction strategy of TNBC is considered to have critical importance in disease management (Bianchini et al, 2016; Bao et al, 2019). Apart from the traditional TNM staging evaluation system, other prognostic biomarkers sporadically proposed by limited sample surveys are likewise deficient in stability and consistency of survival prediction for TNBC (Park et al, 2011). The N6-methyladenosine (m6A) modification plays a critical role in cancer development. Little is known about the m6A modification in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer. The prognostic value of m6A RNA methylation in TNBC deserves exploration
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