Abstract

BackgroundBladder cancer is one of the most mortal cancers. Bladder cancer has distinct gene expression signature, highlighting altered gene expression plays important roles in bladder cancer etiology. However, the mechanism for how the regulatory disorder causes the altered expression in bladder cancer remains elusive. Core promoter controls transcriptional initiation. We hypothesized that mutation in core promoter abnormality could cause abnormal transcriptional initiation thereby the altered gene expression in bladder cancer.MethodsIn this study, we performed a genome-wide characterization of core promoter mutation in 77 Spanish bladder cancer cases.ResultsWe identified 69 recurrent somatic mutations in 61 core promoters of 62 genes and 28 recurrent germline mutations in 20 core promoters of 21 genes, including TERT, the only gene known with core promoter mutation in bladder cancer, and many oncogenes and tumor suppressors. From the RNA-seq data from bladder cancer, we observed altered expression of the core promoter-mutated genes. We further validated the effects of core promoter mutation on gene expression by using luciferase reporter gene assay. We also identified potential drugs targeting the core promoter-mutated genes.ConclusionsData from our study highlights that core promoter mutation contributes to bladder cancer development through altering gene expression.

Highlights

  • IntroductionBladder cancer has distinct gene expression signature, highlighting altered gene expression plays important roles in bladder cancer etiology

  • Bladder cancer is one of the most mortal cancers

  • The cis-elements consist of TFIIB recognition element (BRE), TATA box, Initiator element (Inr), downstream promoter element (DPE) etc. and their

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Summary

Introduction

Bladder cancer has distinct gene expression signature, highlighting altered gene expression plays important roles in bladder cancer etiology. The mechanism for how the regulatory disorder causes the altered expression in bladder cancer remains elusive. We hypothesized that mutation in core promoter abnormality could cause abnormal transcriptional initiation thereby the altered gene expression in bladder cancer. While environmental contaminants and smoking are known to be the risk factors for bladder cancer [3], knowledge about genetic factor contributing to bladder cancer is limited altered expression. Transcriptional initiation is controlled by the basal transcriptional machinery composed of cis- and trans-elements in the core promoter region surrounding the transcriptional start site (TSS) [9]. The cis-elements consist of TFIIB recognition element (BRE), TATA box, Initiator element (Inr), downstream promoter element (DPE) etc. and their

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