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Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer

Kitchen, Mark O.; Bryan, Richard T.; Haworth, Kim E.; Emes, Richard D.; Luscombe, Christopher; Gommersall, Lyndon; Cheng, K. K.; Zeegers, Maurice P.; James, Nicholas D.; Devall, Adam J.; Fryer, Anthony A.; Farrell, William E.

Authors

Mark O. Kitchen

Richard T. Bryan

Kim E. Haworth

RICHARD EMES richard.emes@nottingham.ac.uk
Professor of Bioinformatics

Christopher Luscombe

Lyndon Gommersall

K. K. Cheng

Maurice P. Zeegers

Nicholas D. James

Adam J. Devall

Anthony A. Fryer

William E. Farrell



Contributors

Bing-Hua Jiang
Editor

Abstract

Introduction

Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis.

Methods

Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases.

Results

The ISL1 genes’ promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM).

Conclusions

In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC.

Journal Article Type Article
Publication Date Sep 2, 2015
Journal PLOS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 10
Issue 9
Article Number e0137003
Pages e0137003
APA6 Citation Kitchen, M. O., Bryan, R. T., Haworth, K. E., Emes, R. D., Luscombe, C., Gommersall, L., …Farrell, W. E. (2015). Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer. PLoS ONE, 10(9), e0137003. https://doi.org/10.1371/journal.pone.0137003
DOI https://doi.org/10.1371/journal.pone.0137003
Publisher URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137003
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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