Affiliations: [a] Department of Breast Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China | [b] Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
Correspondence:
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Corresponding author: Ning Liao, Department of Breast Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, No. 106 Zhongshan Er Road, Guangzhou, Guangdong 510080, China. Fax: +86 20 87827812 50910; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: OBJECTIVE: N6-methyladenosine (m6A) is a common RNA modification on eukaryotic mRNA and some of the m6A regulatory proteins play a crucial role in breast cancer. However, the copy number variations for m6A regulatory proteins and their role in clinicopathological characteristics and survival in breast cancer remain unclear. METHODS: In this study, we screened the m6A related genes alterations in breast cancer by analyzing the Molecular Taxonomy of Breast Cancer International Consortium and The Cancer Genome Atlas database, and further analyzed the clinical prognostic value of YTHDF1 amplification. RESULTS: The YTH domain family (YTHDF3 and YTHDF1) amplification exhibited higher alteration rates among 10 m6A regulatory genes. YTHDF1 and YTHDF3 amplification resulted in higher mRNA expression (P< 0.0001). Protein expression of YTHDF1 and YTHDF3 were higher in breast cancer (P< 0.0001). YTHDF1 amplification presented a high correlation with worse clinicopathological characteristics and overall survival in patients with breast cancer. Cox regression analysis showed that YTHDF1 amplification was an independent risk factor for 10-year overall survival in breast cancer (Hazard ratio: 1.663; 95% confidence interval: 1.298–2.131; P< 0.001). Gene set enrichment analysis revealed that the downstream target of YTHDF1 may be related to MYC signaling regulation and T cell differentiation. Moreover, YTHDF1 amplification and high expression resulted in lower immune cell infiltration. YTHDF1 knockdown retrained proliferation, migration and invasion in breast cancer cells in vitro. CONCLUSIONS: We found significant worse clinical characteristics and lower immune infiltrates in patients with YTHDF1 amplification. The findings indicate that YTHDF1 amplification may be a potential target for the treatment of breast cancer.
Keywords: Breast cancer, survival, N6-methyladenosine, YTHDF1, amplification
