Cell-Free SHOX2 DNA Methylation in Blood as a Molecular Staging Parameter for Risk Stratification in Renal Cell Carcinoma Patients: A Prospective Observational Cohort Study

Author:

Jung Maria1,Ellinger Jörg2,Gevensleben Heidrun1,Syring Isabella2,Lüders Christine1,de Vos Luka3,Pützer Svenja1,Bootz Friedrich3,Landsberg Jennifer4,Kristiansen Glen1,Dietrich Dimo3

Affiliation:

1. Institute of Pathology, University Hospital Bonn, Bonn, Germany

2. Department of Urology, University Hospital Bonn, Bonn, Germany

3. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany

4. Department of Dermatology, University Hospital Bonn, Bonn, Germany

Abstract

Abstract 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 SHOX2 gene body methylation quantitatively in circulating cell-free DNA (ccfDNA) and RCC tissues with regard to risk stratification. METHODS The clinical performance of SHOX2 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 SHOX2 ccfDNA methylation to assess disease stage and identify patients at high risk of death. RESULTS SHOX2 gene body methylation was positively correlated with mRNA expression in RCC tissues (training cohort: Spearman ρ = 0.23, P < 0.001). SHOX2 methylation in tissue and plasma strongly correlated with an advanced disease stage (training cohort: ρ = 0.28, P < 0.001; testing cohort/tissue: ρ = 0.40, P < 0.001; testing cohort/plasma: ρ = 0.34, P = 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), P < 0.001; testing cohort/tissue: HR = 1.16 (95% CI, 1.07–1.27), P = 0.001; testing cohort/plasma: HR = 1.50 (95% CI, 1.29–1.74), P < 0.001]. CONCLUSIONS Pretherapeutic SHOX2 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.

Funder

University Hospital Bonn

Publisher

Oxford University Press (OUP)

Subject

Biochemistry, medical,Clinical Biochemistry

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