DNA Methylation Architecture Provides Insight into the Pathogenesis of Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis

Methylation modifications help better understand the pathogenesis of upper tract urothelial carcinoma. A total of 11 eligible studies regarding DNA methylation alterations were included in this meta-analysis. Twelve methy-lated genes were found to be significant in the diagnosis or prognostic outcome of UTUC, including tumor recurrence, progression, and mortality. Candidate biomarkers with essential diagnosis and prognosis function might provide precision medicine references for personalized therapies. Purpose: Numerous studies suggested methylation modifications play an important role in upper tract urothelial carci-noma (UTUC), but few have depicted DNA methylation architecture on the pathological process of UTUC. We aimed to better understand the pathogenesis of UTUC and provide precision medicine references when managing UTUC patients. Methods: PubMed, Cochrane Library, EMBASE, and Scopus were searched for UTUC until December 31, 2020. Methodological quality assessment was conducted according to NIH recommendations. Meta-analysis was conducted to assess the prognostic effect of methylated genes. Kaplan-Meier survival analyses were performed to validate methylated genes and cytosine-phosphate-guanine (CpG) sites. Results: Eleven studies (3619 patients) were eligible to investigate 12 methylated genes and 10 CpGs. The quality of all the studies was fair to good. Meta-analysis found the pooled effect of eligible methylated genes had a low risk of tumor recurrence (HR = 0 middot67; 95% CI: 0 middot51-0 middot87; P = middot003), but a high risk of tumor progression (HR = 1 middot60; 95% CI: 1 middot17-2 middot18; P = middot003) and cancer-specific mortality (HR = 1 middot35; 95% CI: 1 middot06-1 middot72; P = middot01). For individual methylation status of GDF15, HSPA2, RASSF1A, TMEFF2, and VIM, the pooled effect of each gene was found pleiotropic on both diagnosis and prognosis. Survival analysis suggested higher methylation of SPARCL1 had a better disease-specific survival ( P = middot048). Conclusion: We combined meta -analysis and Kaplan-Meier survival analysis using the most updated evidence on the methylation of UTUC. Candidate biomarkers with essential diagnosis and prognosis function might provide precision medicine references for personal-ized therapies.