M6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer.

Abstract

Simple SummaryRecurrence and metastatic progression always lead to dismal outcomes in prostate cancer (PCa). There is no reliable biomarker for the prediction of recurrence and metastasis other than the Prostate Cancer Antigen (PCA). N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is regulated by m6A regulators dynamically. Since m6A modification is associated with cancer development and outgrowth, we performed a consensus clustering on PCa with regard to the gene expression of all m6A regulators. We identified three subtypes of Pca with distinct m6A expression patterns and enriched biological pathways. We also established an m6A score for metastasis prediction based on our clustering, which is potentially a predictive biomarker for Pca metastasis.Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m6A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m6A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m6A regulators. Each subtype’s signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m6A subtypes were predicted by Gene Ontology. The m6A score was developed to predict m6A activation. The association of the m6A score with patients’ survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m6A score to evaluate the m6A regulator activation for PCa. The m6A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m6A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m6A regulators in PCa progression and the m6A score is a promising predictive biomarker for PCa metastasis.