A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer
Stubendorff B, Wilhelm K, Posselt K, Catto J, Hartmann A, Bertz S, Fuessel S, Novotny V, Toma M, Gajda M, Lehmann J, Wunderlich H, Grimm MO, Stoeckle M, Junker K (2019)
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 145
Pages Range: 811-820
Journal Issue: 4
DOI: 10.1007/s00432-018-02829-4
Abstract
PurposeIn 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.MethodsGenome-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.ResultsMicroarray 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).ConclusionsWe 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.
Authors with CRIS profile
Arndt Hartmann
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Simone Bertz
Institute of Pathology
Involved external institutions
Universität des Saarlandes (UdS)
Germany (DE)
Universitätsklinikum Jena
Germany (DE)
Technische Universität Dresden
Germany (DE)
University of Sheffield
United Kingdom (GB)
St. Georg Klinikum Eisenach gemeinnützige GmbH
Germany (DE)
Germany (DE)
Universitätsklinikum Jena
Germany (DE)
Technische Universität Dresden
Germany (DE)
University of Sheffield
United Kingdom (GB)
St. Georg Klinikum Eisenach gemeinnützige GmbH
Germany (DE)
How to cite
APA:
Stubendorff, B., Wilhelm, K., Posselt, K., Catto, J., Hartmann, A., Bertz, S.,... Junker, K. (2019). A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer. Journal of Cancer Research and Clinical Oncology, 145(4), 811-820. https://dx.doi.org/10.1007/s00432-018-02829-4
MLA:
Stubendorff, Beatrice, et al. "A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer." Journal of Cancer Research and Clinical Oncology 145.4 (2019): 811-820.
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