A prognostic signature consisting of N6-methyladenosine modified mRNAs demonstrates clinical potential in prediction of biochemical recurrence and guidance on precision therapy in prostate cancer

Jianming Lu; Jiahong Chen; Zhuoyuan Lin; Qinwei Liu; Chuanfan Zhong; Zhouda Cai; Zhenyu Jia; Weide Zhong; Yingke Liang; Chao Cai

doi:10.1016/j.tranon.2023.101670

A prognostic signature consisting of N6-methyladenosine modified mRNAs demonstrates clinical potential in prediction of biochemical recurrence and guidance on precision therapy in prostate cancer

Transl Oncol. 2023 Jul:33:101670. doi: 10.1016/j.tranon.2023.101670. Epub 2023 Apr 13.

Authors

Jianming Lu¹, Jiahong Chen², Zhuoyuan Lin³, Qinwei Liu⁴, Chuanfan Zhong⁵, Zhouda Cai⁶, Zhenyu Jia⁷, Weide Zhong⁸, Yingke Liang⁹, Chao Cai¹⁰

Affiliations

¹ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Key Laboratory of Urology; Guangzhou, Guangdong 510230, China; Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China.
² Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong 516001, China.
³ Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
⁴ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Key Laboratory of Urology; Guangzhou, Guangdong 510230, China.
⁵ Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China.
⁶ Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China.
⁷ Department of Botany and Plant Sciences, University of California, Riverside, CA 92521, USA.
⁸ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Key Laboratory of Urology; Guangzhou, Guangdong 510230, China; Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China; Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.
⁹ Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China.
¹⁰ Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Key Laboratory of Urology; Guangzhou, Guangdong 510230, China. Electronic address: chaocai85@hotmail.com.

Abstract

Novel biomarkers are urgently needed to improve the prediction of clinical outcomes and guide personalized treatment for prostate cancer (PCa) patients. However, the role of N6-methyladenosine (m6A) modifications in PCa initiation and progression remains largely elusive. In our study, we collected benign Prostate Hyperplasia (BPH), localized PCa, and metastatic PCa samples from patients and performed methylated RNA immunoprecipitation sequencing (MeRIP-Seq) to map m6A-methylated mRNAs. Furthermore, we developed a prognostic signature based on 239 differentially methylated RNAs and the TCGA-PRAD dataset, which can be used to calculate an m6A-modified mRNA (MMM) score for a PCa patient, validated by independent multi-center cohorts. Our findings revealed that differential m6A modifications were positively correlated with altered expressions of mapped m6A-modified mRNAs. Higher MMM scores were associated with shorter times to biochemical recurrence (BCR) in PCa patients, and the MMM scoring system outperformed three well-established signatures in nine independent validation cohorts, as demonstrated by Kaplan-Meier survival analysis, C-index and ROC. Patients who did not respond to androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy were found to have high MMM scores. Two hub genes, TLE1 and PFKL, were confirmed to have m6A sites through MeRIP-qPCR, and their knockdown promoted PCa cell invasion. Bioinformatics analysis of single-cell databases identified cell types with high transcript abundance levels of these two genes. In summary, our study is the first to perform transcriptome-wide m6A mapping in prostate tissues. The translational potential of a prognostic signature, comprising m6A-methylated mRNAs, in predicting clinical outcomes and therapy responses for PCa patients, is demonstrated.

Keywords: Androgen receptor signaling inhibitor; Biochemical recurrence; Immunotherapy; N6-methyladenosine modified mRNA; Prognostic signature; Prostate cancer.