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Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.

ABSTRACT: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10(-6)), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10(-4)). DNA methylation profiles did not differ by recurrence status for the other genes.These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence.Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence.

SUBMITTER: Stott-Miller M

PROVIDER: S-EPMC4082437 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.

Stott-Miller Marni M Zhao Shanshan S Wright Jonathan L JL Kolb Suzanne S Bibikova Marina M Klotzle Brandy B Ostrander Elaine A EA Fan Jian-Bing JB Feng Ziding Z Stanford Janet L JL

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20140409 7

<h4>Background</h4>One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.<h4>Methods</h4>We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer ...[more]

PMID: 24718283

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Project description:Voltage-gated chloride ion channels (CLCs) are transmembrane proteins that maintain chloride ion homeostasis in various cells. Accumulating studies indicated CLCs were related to cell growth, proliferation, and cell cycle. Nevertheless, the role of CLCs in prostate cancer (PCa) has not been systematically profiled. The purpose of this study was to investigate the expression profiles and biofunctions of CLCs genes, and construct a novel risk signature to predict biochemical recurrence (BCR) of PCa patients. We identified five differentially expressed CLCs genes in our cohort and then constructed a signature composed of CLCN2 and CLCN6 through Lasso-Cox regression analysis in the training cohort from the Cancer Genome Atlas (TCGA). The testing and entire cohorts from TCGA and the GSE21034 from the Gene Expression Omnibus (GEO) were used as internal and independent external validation datasets. This signature could divide PCa patients into the high and low risk groups with different prognoses, was apparently correlated with clinical features, and was an independent excellent prognostic indicator. Enrichment analysis indicated our signature was primarily concentrated in cellular process and metabolic process. The expression patterns of CLCN2 and CLCN6 were detected in our own cohort based immunohistochemistry staining, and we found CLCN2 and CLCN6 were highly expressed in PCa tissues compared with benign tissues and positively associated with higher Gleason score and shorter BCR-free time. Functional experiments revealed that CLCN2 and CLCN6 downregulation inhibited cell proliferation, colony formation, invasion, and migration, but prolonged cell cycle and promoted apoptosis. Furthermore, Seahorse assay showed that silencing CLCN2 or CLCN6 exerted potential inhibitory effects on energy metabolism in PCa. Collectively, our signature could provide a novel and robust strategy for the prognostic evaluation and improve treatment decision making for PCa patients.

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Dataset Information

Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.

Publications

Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.

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