Dataset Information

Genetic Variants in the Wnt/?-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

ABSTRACT: Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/?-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/?-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development.A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/?-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls.A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007).Together these findings implicate variants in the Wnt/?-catenin stem cell pathway as having a role in bladder cancer etiology.

SUBMITTER: Pierzynski JA

PROVIDER: S-EPMC5087323 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

Pierzynski Jeanne A JA Hildebrandt Michelle A MA Kamat Ashish M AM Lin Jie J Ye Yuanqing Y Dinney Colin P N CP Wu Xifeng X

The Journal of urology 20150711 6

<h4>Purpose</h4>Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/β-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/β-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have ...[more]

PMID: 26173102

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Project description:Urothelial carcinoma of the bladder is the most frequent bladder cancer affecting more than 400,000 people each year. Histopathologically, it is mainly characterized as muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). Recently, the studies largely driven by consortiums such as TCGA identified the mutational landscape of both MIBC and NMIBC and determined the molecular subtypes of bladder cancer. Because of the exceptionally high rate of mutations in chromatin proteins, bladder cancer is thought to be a disease of chromatin, pointing out to the importance of studying epigenetic deregulation and the regulatory landscape of this cancer. In this study, we have analyzed ATAC-seq data generated for MIBC and integrated our findings with gene expression and DNA methylation data to identify subgroup specific regulatory patterns for MIBC. Our computational analysis revealed three MIBC regulatory clusters, which we named as neuronal, non-neuronal and luminal outlier. We have identified target genes of neuronal regulatory elements to be involved in WNT signaling, while target genes of non-neuronal and luminal outlier regulatory regions were enriched in epithelial differentiation and drug metabolism, respectively. Neuronal regulatory elements were determined to be ß-catenin targets (p value?=?3.59e-08) consisting of genes involved in neurogenesis such as FGF9, and PROX1, and significantly enriched for TCF/LEF binding sites (p value?=?1e-584). Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal (odds ratio?=?31.33, p value?=?1.786e-05). Our results for the first time identify regulatory elements characterizing neuronal bladder cancer and links these neuronal regulatory elements with WNT signaling via mutations in ?-catenin and its destruction complex components.

Dataset Information

Genetic Variants in the Wnt/?-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

Publications

Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

Similar Datasets

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