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.
authors.affiliation: Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Cebrian
authors.forename: Marta
authors.initials: M
authors.lastname: Fierro
authors.forename: Esteban
authors.initials: E
authors.lastname: Orenes-Piñero
authors.forename: Laura
authors.initials: L
authors.lastname: Grau
authors.forename: Patricia
authors.initials: P
authors.lastname: Moya
authors.forename: Thorsten
authors.initials: T
authors.lastname: Ecke
authors.forename: Miguel
authors.initials: M
authors.lastname: Alvarez
authors.forename: Marta
authors.initials: M
authors.lastname: Gil
authors.forename: Ferran
authors.initials: F
authors.lastname: Algaba
authors.forename: Joaquin
authors.initials: J
authors.lastname: Bellmunt
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: James
authors.initials: J
authors.lastname: Catto
authors.forename: Antonio
authors.initials: A
authors.lastname: López-Beltrán
authors.forename: Marta
authors.initials: M
authors.lastname: Sánchez-Carbayo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059648:Kisspeptins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction / Q000379:methods; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000628:therapy
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins