A Systematic Review on Prognostic DNA Methylation Markers for Renal Cell Carcinoma: Are We Moving Forward?

Purpose: In this study, we update 2 previously published systematic reviews on prognostic DNA methylation markers for renal cell carcinoma and provide a comprehensive overview of the latest markers and methylation signatures that merit further validation. Materials and Methods: We performed a systematic literature search of PubMed, EMBASE, and Web of Science including all studies published after our previous systematic review (ie, between March 2017 and December 2021). Data extraction and evaluation using the Reporting Recommendations for Tumor Marker Prognostic Studies criteria and the level of evidence was performed for all 58 included studies. DNA methylation markers were considered promising when findings were validated in more than one study or within multiple cohorts. Results: We identified 11 promising single DNA methylation markers (ie, RUNX3, EVI2A, HHLA2, TACSTD2, KEAP1, LAG3, NSD1, ZNF492, GPR149, LEP, and LEPR), three multimarker panels (ie, (1) RAC2, PLCB2, VAV1 and PARVG; (2) NCKAP1L, EVI2A, and BATF; and (3) GREM1, GATA5, LAD1, NEFH, and NEURL) and 5 DNA methylation signatures. Remarkably, since our previous systematic review, only part of the markers recommended for validation were evaluated in subsequent validation efforts, emphasizing the lack of validation in this field. Conclusion: Validation studies for prognostic DNA methylation markers have been scarce despite previously published recommendations. Nevertheless, since then, other novel DNA methylation markers or signatures have been proposed as promising biomarkers emphasizing the current focus on expanding evidence instead of further building the evidence on specific markers with the aim of clinical translation.