A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer.

In this study, we aimed to identify a DNA methylation pattern suitable for prognosis assessment of muscle-invasive bladder cancer and to investigate metastasis-associated processes regulated by DNA methylation.

Genome-wide methylation analysis was performed on 23 muscle-invasive bladder tumors by microarray analysis. Validation was performed by the qAMP technique in two different patient cohorts (n = 32 and n = 100). mRNA expression was analyzed in 12 samples. Protein expression was determined using tissue microarrays of 291 patients. Bladder cancer cell lines T24 and 253JB-V were used for functional analyses.

Microarray analyses revealed KISS1R, SEPT9 and CSAD as putative biomarkers with hypermethylation in node-positive tumors. The combination of the three genes predicted the metastatic risk with sensitivity of 73% and specificity of 71% in cohort 1, and sensitivity of 82% and specificity of 54% in cohort 2. mRNA expression differences were detected for KISS1R (p = 0.04). Protein expression of KISS1R was significantly reduced (p < 0.001). Knockdown of SEPT9v3 resulted in increased cell migration by 28% (p = 0.04) and increased invasion by 22% (p = 0.004). KISS1R overexpression resulted in decreased cell migration (25%, p = 0.1).

We identified a methylation marker panel suitable to differentiate between patients with positive and negative lymph nodes at time of cystectomy. This enables a risk assessment for patients who potentially benefit from extended lymph node resection as well as from neoadjuvant chemotherapy and could improve the survival rates. Furthermore, we examined the impact of putative markers on tumor behavior. Hence, KISS1R and SEPT9 could represent a starting point for the development of novel therapy approaches.

Journal of cancer research and clinical oncology. 2019 Jan 02 [Epub ahead of print]

Beatrice Stubendorff, Kerstin Wilhelm, Kathleen Posselt, James Catto, Arndt Hartmann, Simone Bertz, Susanne Füssel, Vladimir Novotny, Marieta Toma, Mieczyslaw Gajda, Jan Lehmann, Heiko Wunderlich, Marc-Oliver Grimm, Michael Stöckle, Kerstin Junker

Department of Urology and Pediatric Urology, Saarland University, Kirrberger Strasse, 66421, Homburg/saar, Germany., Department of Urology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany., Department of Urology, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, 01307, Dresden, Germany., The Medical School, University of Sheffield, Institute for Cancer Studies, Beech Hill Rd, S10 2RX, Sheffield, UK., Institute of Pathology, University Hospital Erlangen-Nürnberg, Krankenhausstraße 12, 91054, Erlangen, Germany., Institute of Pathology, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, 01307, Dresden, Germany., Institute of Pathology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany., Clinic of Urology, St. Georg Hospital, Mühlhäuser Str. 94 -95, 99817, Eisenach, Germany., Department of Urology and Pediatric Urology, Saarland University, Kirrberger Strasse, 66421, Homburg/saar, Germany. .

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