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.

Evaluation of KiSS1 as a Prognostic Biomarker in North Indian Breast Cancer Cases

“…The KiSS1 gene is located on chromosome 1 near q32.1 with regulatory elements localized in chromosome 6 at 6q16.3-q23 (Makri et al, 2008) and has four exons of which the 5' and 3' exons are only partly translated (Messager et al, 2005). Off late KiSS1 has been shown to be epigenetically silenced by hypermethylation in bladder cancer (Cebrian et al, 2011) and colorectal cancer (Moya et al, 2013). Data amassed from the literature support the hypothesis that loss of KiSS1 expression has been associated with the progression and metastasis of various tumors, including esophageal, brain, ovarian and melanoma (Li et al, 2012;Sun et al, 2013;Okugawa et al, 2013).…”

Molecular and Epigenetic Mechanism Regulating Hypothalamic <b><i>Kiss1</i></b> Gene Expression in Mammals

“…The 5-azacytidine treatment suppressed methylation of CpG dinucleotides of the putative Kiss1 promoter region (flanking region of the Kiss1 transcriptional start site), suggesting that methylation of the putative Kiss1 promoter region is required for the pubertal increase in Kiss1 gene expression. In several cancer cells, an inverse relationship was found between DNA methylation in the CpG island of the putative KISS1 promoter and KISS1 gene expression [56,57]. However, this inverse relationship may be absent, along with the disappearance of the CpG island in the putative Kiss1 promoter, in rodents, as already pointed out elsewhere [58].…”

Current situation and future usage of anticancer drug databases

“…Realizing the fact that cancers, from different or even the same tissues are distinct in gene alterations and therapy resistance, workers of this database have been dedicated to supporting the development of individual therapies all the time. Furthermore, tumor heterogeneity [6] and its relationship between chemotherapy as well as tumor stratification based on somatic mutations and epigenetic changes [7] will be taken into consideration and become part of a new release of CancerResource. This database is accessible at http://bioinformatics.charite.de/care.…”