Establishment of a Risk Signature Based on m6A RNA Methylation Regulators That Predicts Poor Prognosis in Renal Cell Carcinoma

Jingsun Wei; Yucheng Qian; Yang Tang; Xiaoxu Ge; Kai Jiang; Yimin Fang; Dongliang Fu; Xiangxing Kong; Qian Xiao; Kefeng Ding

doi:10.2147/OTT.S288663

Establishment of a Risk Signature Based on m6A RNA Methylation Regulators That Predicts Poor Prognosis in Renal Cell Carcinoma

Onco Targets Ther. 2021 Jan 14:14:413-426. doi: 10.2147/OTT.S288663. eCollection 2021.

Authors

Jingsun Wei^#^{1

2}, Yucheng Qian^#^{1

2}, Yang Tang^{1

2}, Xiaoxu Ge^{1

2}, Kai Jiang^{1

2}, Yimin Fang^{1

2}, Dongliang Fu^{1

2}, Xiangxing Kong¹, Qian Xiao¹, Kefeng Ding^{1

2}

Affiliations

¹ Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
² Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: N6-methyladenosine (m6A) modifications represent one of the most common methylation modifications, and they are mediated by m6A RNA methylation regulators. However, their functions in renal cell carcinoma (RCC) are not completely understood. The aim of this study was to investigate the effects of the regulators in RCC.

Materials and methods: The expression levels of the 13 main m6A RNA methylation regulators in RCC were detected and consensus clustering was performed to explore their relationships with RCC. Thereafter, a risk signature based on the regulators was established. This risk model was fully verified by conducting prognostic analyses using two datasets (The Cancer Genome Atlas [TCGA] and Gene Expression Omnibus [GEO] datasets) and a ROC curve analysis.

Results: Of the 13 main m6A regulators, six were significantly upregulated and four were significantly downregulated in 893 RCC cases compared to 128 normal controls in the TCGA database. Consensus clustering based on the regulators identified two clusters of RCC cases, which were significantly associated with a pathological characteristic (T status). Thus, these results indicated that m6A RNA methylation regulators were associated with RCC. Thereafter, a risk model involving two of the regulators (METTL14 and WTAP) was established. The alterations in the mRNA and protein expression levels of these two regulators were further confirmed based on Human Protein Atlas data and real-time PCR in RCC and normal cell lines. The results indicated that the risk model may serve as an independent prognostic marker of overall survival, and it was also associated with clinicopathological characteristics (T status, M status, pathological stage, and gender) in RCC.

Conclusion: Collectively, the results of this study indicated that the risk model (based on two m6A RNA methylation regulators) may serve as an independent prognostic indicator of RCC, which may aid further investigation into m6A RNA modification in RCC.

Keywords: TCGA; m6A methylation; prognostic signature; renal cell carcinoma.

Grants and funding

This study was funded by the National Key R&D Program of China (2017YFC0908200), the Key Technology Research and Development Program of Zhejiang Province (2017C03017), and the National Natural Science Foundation of China (81772545).