Effect of N6-Methyladenosine Regulators on Progression and Prognosis of Triple-Negative Breast Cancer

Shanshan Wang; Xuan Zou; Yajie Chen; William C Cho; Xiang Zhou

doi:10.3389/fgene.2020.580036

Effect of N6-Methyladenosine Regulators on Progression and Prognosis of Triple-Negative Breast Cancer

Front Genet. 2021 Jan 28:11:580036. doi: 10.3389/fgene.2020.580036. eCollection 2020.

Authors

Shanshan Wang^{1

2}, Xuan Zou^{2

3}, Yajie Chen^{2

4}, William C Cho⁵, Xiang Zhou^{1

2

6

7}

Affiliations

¹ Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
⁵ Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
⁶ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁷ Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

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.

Keywords: N6-methyladenosine; TNBC; nomogram; prognosis; progression.