KISS1 methylation and expression as tumor stratification biomarkers and clinical outcome prognosticators for bladder cancer patients Journal Article


Authors: Cebrian, V.; Fierro, M.; Orenes-Piero, E.; Grau, L.; Moya, P.; Ecke, T.; Alvarez, M.; Gil, M.; Algaba, F.; Bellmunt, J.; Cordon-Cardo, C.; Catto, J.; Lopez-Beltran, A.; Sanchez Carbayo, M.
Article Title: KISS1 methylation and expression as tumor stratification biomarkers and clinical outcome prognosticators for bladder cancer patients
Abstract: KISS1 is a metastasis suppressor gene that is lost in several malignancies, including bladder cancer. We tested the epigenetic silencing hypothesis and evaluated the biological influence of KISS1 methylation on its expression and clinical relevance in bladder cancer. KISS1 hypermethylation was frequent in bladder cancer cells analyzed by methylation-specific PCR and bisulfite sequencing and was associated with low gene expression, being restored in vitro by demethylating azacytidine. Hypermethylation was also frequently observed in a large series of bladder tumors (83.1%, n = 804). KISS1 methylation was associated with increasing stage (P = 0.001) and tumor grade (P = 0.010). KISS1 methylation was associated with low KISS1 transcript expression by quantitative RT-PCR (P = 0.037). KISS1 transcript expression was also associated with histopathological tumor stage (P < 0.0005). Low transcript expression alone (P = 0.003) or combined with methylation (P = 0.019) was associated with poor disease-specific survival (n = 205). KISS1 transcript expression remained an independent prognosticator in multivariate analyses (P = 0.017). KISS1 hypermethylation was identified in bladder cancer, providing a potential mechanistic explanation (epigenetic silencing) for the observed loss of KISS1 in uroepithelial malignancies. Associations of KISS1 methylation and its expression with histopathological variables and poor survival suggest the utility of incorporating KISS1 measurement using paraffin-embedded material for tumor stratification and clinical outcome prognosis of patients with uroepithelial neoplasias. © 2011 American Society for Investigative Pathology.
Keywords: adult; cancer survival; controlled study; protein expression; treatment outcome; aged; aged, 80 and over; disease-free survival; middle aged; human cell; major clinical study; histopathology; cancer patient; outcome assessment; polymerase chain reaction; biological marker; reverse transcription polymerase chain reaction; gene expression; in vitro study; bladder cancer; dna methylation; urinary bladder neoplasms; gene expression regulation, neoplastic; molecular sequence data; epigenetics; cpg islands; epigenesis, genetic; cancer cell; neoplasm metastasis; base sequence; gene silencing; protein methylation; sequence analysis, dna; bisulfite; metastin; kisspeptins
Journal Title: American Journal of Pathology
Volume: 179
Issue: 2
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2011-08-01
Start Page: 540
End Page: 546
Language: English
DOI: 10.1016/j.ajpath.2011.05.009
PROVIDER: scopus
PMCID: PMC3157173
PUBMED: 21683672
DOI/URL:
Notes: --- - "Export Date: 3 October 2011" - "CODEN: AJPAA" - "Source: Scopus"
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