Cell-Free DNA Methylation in Blood as a Molecular Staging Parameter for Risk Stratification in Renal Cell Carcinoma Patients: A Prospective Observational Cohort Study.

BACKGROUND: Novel targeted treatments and immunotherapies have substantially changed therapeutic options for advanced and metastatic renal cell carcinomas (RCCs). However, accurate diagnostic tests for the identification of high-risk patients are urgently needed. Here, we analyzed SHOX2 mRNA expression in RCC tissues and gene body methylation quantitatively in circulating cell-free DNA (ccfDNA) and RCC tissues with regard to risk stratification.

METHODS: The clinical performance of methylation was tested retrospectively and prospectively in a training and testing cohort of RCC tissue samples (n = 760 in total). SHOX2 mRNA expression analysis was included in the training cohort. In matched blood plasma samples from the testing cohort (n = 100), we prospectively examined the capability of pretherapeutic quantitative ccfDNA methylation to assess disease stage and identify patients at high risk of death.

RESULTS: gene body methylation was positively correlated with mRNA expression in RCC tissues (training cohort: Spearman ρ = 0.23, < 0.001). methylation in tissue and plasma strongly correlated with an advanced disease stage (training cohort: ρ = 0.28, < 0.001; testing cohort/tissue: ρ = 0.40, < 0.001; testing cohort/plasma: ρ = 0.34, = 0.001) and risk of death after initial partial or radical nephrectomy [training cohort: hazard ratio (HR) = 1.40 (95% CI, 1.24-1.57), < 0.001; testing cohort/tissue: HR = 1.16 (95% CI, 1.07-1.27), = 0.001; testing cohort/plasma: HR = 1.50 (95% CI, 1.29-1.74), < 0.001].

CONCLUSIONS: Pretherapeutic ccfDNA methylation testing allows for the identification of RCC patients at high risk of death after nephrectomy. These patients might benefit from an adjuvant treatment or early initiation of a palliative treatment.

© 2018 American Association for Clinical Chemistry.

PMID: 30626634