Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study

Andrew Beggs; Samir Mehta; Jonathan Deeks; Jonathan D.  James; Germaine Caldwell; Mark Dilworth; Joanne Stockton; Daniel Blakeway; Valerie Pestinger; Alexandra Vince; Phillipe Taniere; Tariq Iqbal; Laura Magill; Glenn Matthews; Dion Morton

doi:10.1016/j.ebiom.2018.11.034

Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study

Andrew Beggs, Samir Mehta, Jonathan Deeks, Jonathan D. James, Germaine Caldwell, Mark Dilworth, Joanne Stockton, Daniel Blakeway, Valerie Pestinger, Alexandra Vince, Phillipe Taniere, Tariq Iqbal, Laura Magill, Glenn Matthews, Dion Morton

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Abstract

Background: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasivemalignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort.
Methods: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from35 patients with cancer, 78with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa.
Findings: For neoplasticmucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC=0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC=0.88; (0.84, 0.91).
For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC=0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant nonneoplastic colonic mucosa.
Interpretation: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial.
Funding: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).

Original language	English
Pages (from-to)	265-271
Number of pages	7
Journal	EBioMedicine
Volume	39
Early online date	22 Nov 2018
DOIs	https://doi.org/10.1016/j.ebiom.2018.11.034
Publication status	Published - 1 Jan 2019

Bibliographical note

Keywords

Biomarkers, Tumor/genetics
Colitis, Ulcerative/complications
Colonic Neoplasms/diagnosis
DNA Methylation
Epigenesis, Genetic
Female
Humans
Male
Prospective Studies
Retrospective Studies
Sequence Analysis, DNA/methods

UN SDGs

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

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10.1016/j.ebiom.2018.11.034Licence: Creative Commons: Attribution (CC BY)

Beggs_et_al_Validation_of_epigenetic_markers_EBioMedicine_2018
Checked for eligibility 28/11/2018 https://doi.org/10.1016/j.ebiom.2018.11.034
Final published version, 603 KBLicence: Creative Commons: Attribution (CC BY)

https://www.sciencedirect.com/science/article/pii/S2352396418305383Licence: Creative Commons: Attribution (CC BY)

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Beggs, A., Mehta, S., Deeks, J., James, J. D., Caldwell, G., Dilworth, M., Stockton, J., Blakeway, D., Pestinger, V., Vince, A., Taniere, P., Iqbal, T., Magill, L., Matthews, G., & Morton, D. (2019). Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study. EBioMedicine, 39, 265-271. https://doi.org/10.1016/j.ebiom.2018.11.034

@article{17f69136381d46e0b62e8e8ad632a0d2,

title = "Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study",

abstract = "Background: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasivemalignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort.Methods: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from35 patients with cancer, 78with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa.Findings: For neoplasticmucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC=0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC=0.88; (0.84, 0.91).For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC=0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant nonneoplastic colonic mucosa.Interpretation: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial.Funding: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).",

keywords = "Biomarkers, Tumor/genetics, Colitis, Ulcerative/complications, Colonic Neoplasms/diagnosis, DNA Methylation, Epigenesis, Genetic, Female, Humans, Male, Prospective Studies, Retrospective Studies, Sequence Analysis, DNA/methods",

author = "Andrew Beggs and Samir Mehta and Jonathan Deeks and James, {Jonathan D.} and Germaine Caldwell and Mark Dilworth and Joanne Stockton and Daniel Blakeway and Valerie Pestinger and Alexandra Vince and Phillipe Taniere and Tariq Iqbal and Laura Magill and Glenn Matthews and Dion Morton",

year = "2019",

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doi = "10.1016/j.ebiom.2018.11.034",

language = "English",

volume = "39",

pages = "265--271",

journal = "EBioMedicine",

issn = "2352-3964",

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}

Beggs, A , Mehta, S , Deeks, J, James, JD, Caldwell, G, Dilworth, M , Stockton, J, Blakeway, D, Pestinger, V, Vince, A, Taniere, P, Iqbal, T , Magill, L, Matthews, G & Morton, D 2019, 'Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study', EBioMedicine, vol. 39, pp. 265-271. https://doi.org/10.1016/j.ebiom.2018.11.034

TY - JOUR

T1 - Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study

AU - Beggs, Andrew

AU - Mehta, Samir

AU - Deeks, Jonathan

AU - James, Jonathan D.

AU - Caldwell, Germaine

AU - Dilworth, Mark

AU - Stockton, Joanne

AU - Blakeway, Daniel

AU - Pestinger, Valerie

AU - Vince, Alexandra

AU - Taniere, Phillipe

AU - Iqbal, Tariq

AU - Magill, Laura

AU - Matthews, Glenn

AU - Morton, Dion

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasivemalignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort.Methods: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from35 patients with cancer, 78with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa.Findings: For neoplasticmucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC=0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC=0.88; (0.84, 0.91).For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC=0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant nonneoplastic colonic mucosa.Interpretation: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial.Funding: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).

AB - Background: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasivemalignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort.Methods: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from35 patients with cancer, 78with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa.Findings: For neoplasticmucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC=0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC=0.88; (0.84, 0.91).For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC=0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant nonneoplastic colonic mucosa.Interpretation: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial.Funding: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).

KW - Biomarkers, Tumor/genetics

KW - Colitis, Ulcerative/complications

KW - Colonic Neoplasms/diagnosis

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Female

KW - Humans

KW - Male

KW - Prospective Studies

KW - Retrospective Studies

KW - Sequence Analysis, DNA/methods

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U2 - 10.1016/j.ebiom.2018.11.034

DO - 10.1016/j.ebiom.2018.11.034

M3 - Article

C2 - 30473377

SN - 2352-3964

VL - 39

SP - 265

EP - 271

JO - EBioMedicine

JF - EBioMedicine

ER -

Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study

Abstract

Bibliographical note

Keywords

UN SDGs

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