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

Beggs, Andrew D
; 
Mehta, Samir
; 
Deeks, Jonathan J
; 
James, Jonathan D
; 
Caldwell, Germaine M
; 
Dilworth, Mark P
; 
Stockton, Joanne D
; 
Blakeway, Daniel
; 
Pestinger, Valerie
; 
Vince, Alexandra
... show 10 more
Authors
Beggs, Andrew D
 Mehta, Samir
 Deeks, Jonathan J
 James, Jonathan D
 Caldwell, Germaine M
 Dilworth, Mark P
 Stockton, Joanne D
 Blakeway, Daniel
 Pestinger, Valerie
 Vince, Alexandra
 Taniere, Phillipe
 Iqbal, Tariq
 Magill, Laura
 Matthews, Glenn
 Mortona, Dion G
 Antonio, Peter
 Brown, James P
 Deeks, Jon
 Howard, Rebecca
 Johnson, Steve
 Magill, Laura
 Mehta, Samir
 Sheward, Nicholas
 Vince, Alexandra
 Langman, Gerald
 Sharma, Naveen K
 Beggs, Andrew D
 Blakeway, Daniel
 Caldwell, Germaine M
 Dilworth, Mark P
 James, Jonathan D
 Matthews, Glenn M
 Pestinger, Valerie
 Stockton, Joanne D
 Cooney, Rachel M
 Frost, John
 Hussainy, Akbar
 Mistry, Rita
 Muzaffar, Suhail
 Cooper, Sheldon C
 De Silva, Shanika D
 Gillett, Robert
 Slater, Jayne
 Brookes, Matthew
 Green, Marie
 Mangalika, Manel
 Widlak, Monika
 Breckles, Lisa
 Ghods, Manijeh
 Iqbal, Tariq H
 Iqbal, Virginia
 Morton, Dion G
 Pinkney, Thomas D
 Suggett, Nigel R
 Taniere, Philippe
 Arndtz, Katherine
 Awasthi, Ashish K
 Begum, Kolsuma
 Cvijan, Dragana
 Nahal, Jasbir
 Collaborative, ENDCAP-C Module 1
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Other contributors
Affiliation
Epub Date
Issue Date
2018-11-22
Submitted date
Subjects
ENDCAP-C Module 1 Collaborative
 Humans
 Colonic Neoplasms
 Colitis, Ulcerative
 Retrospective Studies
 Prospective Studies
 Sequence Analysis, DNA
 DNA Methylation
 Epigenesis, Genetic
 Female
 Male
 Biomarkers, Tumor
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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 invasive malignancy 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 from 35 patients with cancer, 78 with 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 neoplastic mucosa 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 non-neoplastic 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).
Citation
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, pp. 265-271. https://doi.org/10.1016/j.ebiom.2018.11.034
Publisher
Elsevier
Journal
EBioMedicine
Research Unit
URI
http://hdl.handle.net/2436/623036
DOI
10.1016/j.ebiom.2018.11.034
PubMed ID
30473377
PubMed Central ID
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https://www.sciencedirect.com/science/article/pii/S2352396418305383?via%3Dihub
Type
Journal article
Language
en
Description
Series/Report no.
ISSN
2352-3964
EISSN
2352-3964
ISBN
ISMN
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Sponsors
The ENDCAP-C study was funded by the Efficacy and Mechanism Evaluation (EME) Programme (11/100/29), an MRC and NIHR partnership. Assay development supported by Birmingham Experimental Medicine Cancer Centre. AB acknowledges funding from the Wellcome Trust (102732/Z/13/Z), Cancer Research UK (C31641/A23923) and the Medical Research Council (MR/M016587/1). JJD and DGM received support as an NIHR Senior Investigator and JJD from the NIHR Birmingham Biomedical Research Centre.
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Licence for published version: Creative Commons Attribution 4.0 International
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