Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer: A Systematic Review to Identify Loci for Prospective Validation

Pratik M.S. Gurung; Abigail R. Barnett; Jayne S. Wilson; John Hudson; Douglas G. Ward; Edward M. Messing; Richard T. Bryan

doi:10.1016/j.euf.2019.02.012

Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer: A Systematic Review to Identify Loci for Prospective Validation

Pratik M.S. Gurung, Abigail R. Barnett, Jayne S. Wilson, John Hudson, Douglas G. Ward, Edward M. Messing, Richard T. Bryan^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

3 Citations (Scopus)

13 Downloads (Pure)

Abstract

Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.

Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.

Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.

Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).

Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.

Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.

Original language	English
Pages (from-to)	683-697
Number of pages	15
Journal	European Urology Focus
Volume	6
Issue number	4
Early online date	23 Feb 2019
DOIs	https://doi.org/10.1016/j.euf.2019.02.012
Publication status	Published - 15 Jul 2020

Bibliographical note

Publisher Copyright:
© 2019 European Association of Urology

Keywords

Biomarkers
DNA
High-risk non–muscle-invasive bladder cancer
Methylation
molecular markers
Prognostic markers
Systematic review

ASJC Scopus subject areas

Urology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.euf.2019.02.012Licence: None: All rights reserved

Gurung_et_al_Prognostic_DNA_methylation_European_Urulogy_Focus_2019
Checked for eligibility 11/02/2019 Published in European Urology Focus https://www.journals.elsevier.com/european-urology-focus
Accepted author manuscript, 1.9 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

Molecular Markers for non muscle invasive bladder cancer
James, N. (Principal Investigator), Bryan, R. (Co-Investigator), Deshmukh, N. (Co-Investigator), Zeegers, M. (Co-Investigator), Murray, P. (Co-Investigator), Riley, R. (Co-Investigator) & Cheng, K. (Co-Investigator)
UHB CHARITABLE FUNDS
30/07/12 → 29/04/17
Project: Research

Cancer and Genomic Sciences (Organisational unit)
Bryan, R. (Advisor)
16 Sept 2015 → …
Activity: Membership › Membership of working group or committee

Cite this

@article{3ce5a3d523fa4b6eac35da067b3adbbd,

title = "Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer: A Systematic Review to Identify Loci for Prospective Validation",

abstract = "Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Gu{\'e}rin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.",

keywords = "Biomarkers, DNA, High-risk non–muscle-invasive bladder cancer, Methylation, molecular markers, Prognostic markers, Systematic review",

author = "Gurung, {Pratik M.S.} and Barnett, {Abigail R.} and Wilson, {Jayne S.} and John Hudson and Ward, {Douglas G.} and Messing, {Edward M.} and Bryan, {Richard T.}",

note = "Publisher Copyright: {\textcopyright} 2019 European Association of Urology",

year = "2020",

month = jul,

day = "15",

doi = "10.1016/j.euf.2019.02.012",

language = "English",

volume = "6",

pages = "683--697",

journal = "European Urology Focus",

issn = "2405-4569",

publisher = "Elsevier",

number = "4",

}

TY - JOUR

T1 - Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer

T2 - A Systematic Review to Identify Loci for Prospective Validation

AU - Gurung, Pratik M.S.

AU - Barnett, Abigail R.

AU - Wilson, Jayne S.

AU - Hudson, John

AU - Ward, Douglas G.

AU - Messing, Edward M.

AU - Bryan, Richard T.

PY - 2020/7/15

Y1 - 2020/7/15

N2 - Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.

AB - Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.

KW - Biomarkers

KW - DNA

KW - High-risk non–muscle-invasive bladder cancer

KW - Methylation

KW - molecular markers

KW - Prognostic markers

KW - Systematic review

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DO - 10.1016/j.euf.2019.02.012

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SN - 2405-4569

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Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer: A Systematic Review to Identify Loci for Prospective Validation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Projects

Molecular Markers for non muscle invasive bladder cancer

Activities

Cancer and Genomic Sciences (Organisational unit)

Cite this