In silico DNA methylation analysis identifies potential prognostic biomarkers in type 2 papillary renal cell carcinoma.

Abstract

There are currently no effective treatments for advanced‐stage papillary renal cell carcinoma (PRCC). The goal of this study is to define potential DNA methylation‐based markers and treatment targets for advanced‐stage type 2 PRCC. Progressive DNA methylation changes and copy number variation (CNV) from localized to advanced‐stage type 2 PRCC are analyzed by using methylation data generated by TCGA's kidney renal papillary cell carcinoma (TCGA‐KIRP, 450k array) project. Survival analyses are performed for the identified biomarkers and genes with CNV. In addition, expression of the corresponding genes is investigated by RNA‐seq analysis. Progressive methylation changes in several CpGs from localized to advanced‐stage type 2 PRCC are observed. Four CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) in particular are identified as markers for differentiating between localized and advanced‐stage type 2 PRCC. Copy number analysis reveals that copy gain of PTK7 mostly occurs in advanced‐stage type 2 PRCC. Both the four CpG methylation changes and PTK7 copy number gain are associated with patient survival. RNA‐seq analysis demonstrates that PTK7 copy gain leads to higher PTK7 expression relative to tumors without copy number gain. Moreover, PTK7 is significantly upregulated from localized to advanced‐stage type 2 PRCC and is linked to cancer cell invasion. In conclusion, DNA methylation markers that differentiate between localized and advanced‐stage type 2 PRCC may serve as useful markers for disease staging or outcome, while PTK7 copy gain represents a potential treatment target for advanced‐stage type 2 PRCC. Stepwise methylation changes and copy number gain also associate with disease stage in PRCC patients.