Dataset Information

Analysis of bladder cancer tumor CpG methylation and gene expression within The Cancer Genome Atlas identifies GRIA1 as a prognostic biomarker for basal-like bladder cancer.

ABSTRACT: Increased methylation levels at cytosines proximal to guanines (CpG) in the promoter regions of tumor suppressor genes have been reported to play an important role in the development and progression of bladder cancer. In this study, we conducted a genome-wide analysis using data from The Cancer Genome Atlas to better characterize CpG methylation and mRNA expression patterns in urothelial carcinomas and to identify new epigenetic biomarkers of survival. Across 408 tumors, we identified 223 genes that displayed significant relationships between CpG methylation and mRNA expression levels. Hypermethylation within 200 base pairs upstream of the transcription start site and hypomethylation within the 3' untranslated region and body region were associated with gene silencing. These 223 genes were functionally enriched for their role in glutamate receptor signaling and among them was a novel, tumor-stage-independent epigenetic biomarker of overall mortality, GRIA1. GRIA1 hypermethylation and elevated mRNA expression levels were associated with significantly worse survival outcomes in patients with basal-like urothelial carcinomas. Furthermore, 70 genes associated with glutamate receptor signaling were differentially expressed between basal (n = 203 tumors) and luminal (n = 205 tumors) subtypes of bladder cancer, including genes involved in glutamate receptor-mediated activation of the calmodulin, PI3K/Akt, and EGFR signaling pathways. The majority of genes displayed increased expression levels in basal-like subtypes. This research highlights glutamate receptors as targets for investigation in the development and pharmacological treatment of urothelial cancer.

SUBMITTER: Tilley SK

PROVIDER: S-EPMC5622220 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Analysis of bladder cancer tumor CpG methylation and gene expression within The Cancer Genome Atlas identifies <i>GRIA1</i> as a prognostic biomarker for basal-like bladder cancer.

Tilley Sloane K SK Kim William Y WY Fry Rebecca C RC

American journal of cancer research 20170901 9

Increased methylation levels at cytosines proximal to guanines (CpG) in the promoter regions of tumor suppressor genes have been reported to play an important role in the development and progression of bladder cancer. In this study, we conducted a genome-wide analysis using data from The Cancer Genome Atlas to better characterize CpG methylation and mRNA expression patterns in urothelial carcinomas and to identify new epigenetic biomarkers of survival. Across 408 tumors, we identified 223 genes ...[more]

PMID: 28979808

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Project description:PurposeBladder cancer (BLCA) is one of the most common cancers worldwide. In a large proportion of BLCA patients, disease recurs and/or progress after resection, which remains a major clinical issue in BLCA management. Therefore, it is vital to identify prognostic biomarkers for treatment stratification. We investigated the efficiency of CpG methylation for the potential to be a prognostic biomarker for patients with BLCA.Patients and methodsOverall, 357 BLCA patients from The Cancer Genome Atlas (TCGA) were randomly separated into the training and internal validation cohorts. Least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) were used to select candidate CpGs and build the methylation risk score model, which was validated for its prognostic value in the validation cohort by Kaplan-Meier analysis. Hazard curves were generated to reveal the risk nodes throughout the follow-up. Gene Set Enrichment Analysis (GSEA) was used to reveal the potential biological pathways associated with the methylation model. Quantitative real-time polymerase chain reaction (PCR) and western blotting were performed to verify the expression level of the methylated genes.ResultsAfter incorporating the CpGs obtained by the two algorithms, CpG methylation of eight genes corresponding to TNFAIP8L3, KRTDAP, APC, ZC3H3, COL9A2, SLCO4A1, POU3F3, and ADARB2 were prominent candidate predictors in establishing a methylation risk score for BLCA (MRSB), which was used to divide the patients into high- and low-risk progression groups (p < 0.001). The effectiveness of the MRSB was validated in the internal cohort (p < 0.001). In the MRSB high-risk group, the hazard curve exhibited an initial wide, high peak within 10 months after treatment, whereas some gentle peaks around 2 years were noted. Furthermore, a nomogram comprising MRSB, age, sex, and tumor clinical stage was developed to predict the individual progression risk, and it performed well. Survival analysis implicated the effectiveness of MRSB, which remains significant in all the subgroup analysis based on the clinical features. A functional analysis of MRSB and the corresponding genes revealed potential pathways affecting tumor progression. Validation of quantitative real-time PCR and western blotting revealed that TNFAIP8L3 was upregulated in the BLCA tissues.ConclusionWe developed the MRSB, an eight-gene-based methylation signature, which has great potential to be used to predict the post-surgery progression risk of BLCA.

Project description:Objective and Impact Statement. Identifying benign mimics of prostatic adenocarcinoma remains a significant diagnostic challenge. In this work, we developed an approach based on label-free, high-resolution molecular imaging with multispectral deep ultraviolet (UV) microscopy which identifies important prostate tissue components, including basal cells. This work has significant implications towards improving the pathologic assessment and diagnosis of prostate cancer. Introduction. One of the most important indicators of prostate cancer is the absence of basal cells in glands and ducts. However, identifying basal cells using hematoxylin and eosin (H&E) stains, which is the standard of care, can be difficult in a subset of cases. In such situations, pathologists often resort to immunohistochemical (IHC) stains for a definitive diagnosis. However, IHC is expensive and time-consuming and requires more tissue sections which may not be available. In addition, IHC is subject to false-negative or false-positive stains which can potentially lead to an incorrect diagnosis. Methods. We leverage the rich molecular information of label-free multispectral deep UV microscopy to uniquely identify basal cells, luminal cells, and inflammatory cells. The method applies an unsupervised geometrical representation of principal component analysis to separate the various components of prostate tissue leading to multiple image representations of the molecular information. Results. Our results show that this method accurately and efficiently identifies benign and malignant glands with high fidelity, free of any staining procedures, based on the presence or absence of basal cells. We further use the molecular information to directly generate a high-resolution virtual IHC stain that clearly identifies basal cells, even in cases where IHC stains fail. Conclusion. Our simple, low-cost, and label-free deep UV method has the potential to improve and facilitate prostate cancer diagnosis by enabling robust identification of basal cells and other important prostate tissue components.

Dataset Information

Analysis of bladder cancer tumor CpG methylation and gene expression within The Cancer Genome Atlas identifies GRIA1 as a prognostic biomarker for basal-like bladder cancer.

Publications

Analysis of bladder cancer tumor CpG methylation and gene expression within The Cancer Genome Atlas identifies <i>GRIA1</i> as a prognostic biomarker for basal-like bladder cancer.

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