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HumanMethylation450K array–identified biomarkers predict tumour recurrence/progression at initial diagnosis of high-risk non-muscle Invasive bladder cancer

Kitchen, Mark O.; Bryan, Richard T.; Emes, Richard D.; Luscombe, Christopher J.; Cheng, K.K.; Zeegers, Maurice P.; James, Nicholas D.; Gommersall, Lyndon M.; Fryer, Anthony A.

Authors

Mark O. Kitchen

Richard T. Bryan

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

Christopher J. Luscombe

K.K. Cheng

Maurice P. Zeegers

Nicholas D. James

Lyndon M. Gommersall

Anthony A. Fryer



Abstract

Background: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery.
Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management.
Patients and methods: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/ or progression despite BCG) were also assessed by bisulphite Pyrosequencing.
Results: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HRNMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values.
Conclusions: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease

Citation

Kitchen, M. O., Bryan, R. T., Emes, R. D., Luscombe, C. J., Cheng, K., Zeegers, M. P., …Fryer, A. A. (in press). HumanMethylation450K array–identified biomarkers predict tumour recurrence/progression at initial diagnosis of high-risk non-muscle Invasive bladder cancer. Biomarkers in Cancer,

Journal Article Type Article
Acceptance Date Nov 15, 2017
Online Publication Date Jan 8, 2018
Deposit Date Apr 20, 2018
Publicly Available Date Apr 20, 2018
Journal Biomarkers in Cancer
Electronic ISSN 1179-299X
Publisher Libertas Academica
Peer Reviewed Peer Reviewed
Keywords high-risk non-muscle invasive bladder cancer, epigenetics, methylation, HumanMethylation450 BeadChip array, prognostic
biomarker
Public URL http://eprints.nottingham.ac.uk/id/eprint/51274
Publisher URL http://journals.sagepub.com/doi/10.1177/1179299X17751920
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc/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-nc/4.0





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