J Cancer 2019; 10(22):5447-5459. doi:10.7150/jca.35053

Research Paper

N6-methyladenosine-related Genomic Targets are Altered in Breast Cancer Tissue and Associated with Poor Survival

Liwen Liu1,2*, Xin Liu1,2*, Zihui Dong1,2, Jianhao Li1,2, Yan Yu1,2, Xiaolong Chen1,2, Fang Ren2, Guangying Cui1,2, Ranran Sun1,2,3✉

1. Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
2. Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
3. National Engineering Laboratory for Internet Medical System and Application, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
*These authors contributed equally to this work.

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Citation:
Liu L, Liu X, Dong Z, Li J, Yu Y, Chen X, Ren F, Cui G, Sun R. N6-methyladenosine-related Genomic Targets are Altered in Breast Cancer Tissue and Associated with Poor Survival. J Cancer 2019; 10(22):5447-5459. doi:10.7150/jca.35053. Available from http://www.jcancer.org/v10p5447.htm

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Abstract

Purpose: The ectopic expression of N6-methyladenosine (m6A) associated genes is a common feature of multiple tumors. However, little is known about the expression status and the prognostic value of these genes in human breast cancer (BRC). Herein, we conducted a comprehensive analysis to identify the expression profiling and clinical significance of m6A-related genomic targets in BRC.

Materials and Methods: The expression data including 1109 BRC tissues and 113 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA) database to evaluate the mRNA expression levels of m6A-related genomic targets. In addition, 6 independent BRCA cohorts retrieved from the Gene Expression Omnibus (GEO) database were enrolled to further ascertain the expression profiling of m6A-related genomic targets. Meanwhile, the immunohistochemical (IHC) staining data from BRC tissue microarray (TMA) cohort and the Human Protein Atlas (HPA) database were used to evaluate the proteomic expression of m6A-related genomic targets. Immunofluorescence (IF) analysis was performed to validate the subcellular location of m6A-related genomic targets. Moreover, the prognostic value of m6A-related genomic targets in BRC was analyzed by Kaplan-Meier analysis and Cox regression models.

Results: m6A-related genomic targets were differentially expressed in BRC tissues. TMA IHC staining showed that most of the m6A-related genomic targets were significantly altered at the protein level (either upregulated or downregulated), consistent with their changes in the genomic profile. IF analysis showed the subcellular location of m6A-related genomic targets in BRC cell lines. Furthermore, we demonstrated that overexpression of YTHDF1 (P=0.049), YTHDF3 (P<0.001) and KIAA1429 (P=0.032) predicted poor prognosis in terms of overall survival (OS). Upregulation of YTHDF3 was an independent prognostic factor for OS in patients with BRC (P=0.036).

Conclusion: m6A-related genomic targets are significantly altered in BRC and predict poor prognosis. These m6A-related genomic targets could serve as novel prognostic biomarkers for BRC.

Keywords: N6-methyladenosine, Breast cancer, YTHDF3, Prognosis, Biomarkers.