Enhanced neoplasia detection in chronic ulcerative colitis:  the ENDCaP-C diagnostic accuracy study

Ashish Awasthi; Jamie Barbour; Andrew Beggs; Pradeep Bhandari; Daniel Blakeway; Matthew Brookes; James Brown; Matthew Brown; Germaine Caldwell; Samuel Clokie; Ben Colleypriest; Abby Conlin; Shanika de Silva; John de Caestecker; Jonathan Deeks; Anjan Dhar; Mark Dilworth; Edward Fogden; Stephen Foley; Deb Ghosh; Leonie Grellier; Ailsa Hart; Syed Samiul Hoque; Marietta Iacucci; Tariq Iqbal; Jonathan James; Mark Jarvis; Anthoor Jayaprakash; Satish Keshav; Laura Magill; Glenn Matthews; Joel Mawdsley; Simon McLaughlin; Samir Mehta; Kevin Monahan; Dion Morton; Senthil Murugesan; Miles Parkes; Valerie Pestinger; Chris Probert; Arvind Ramadas; Alessandro Rettino; Shaji Sebastian; Naveen Sharma; Michael Griffiths; Joanne Stockton; Venkat Subramanian; Nigel Suggett; Philippe Taniere; Julian Teare; Ajay M Verma; Yvonne Wallis

doi:10.3310/eme08010

Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study

Ashish Awasthi, Jamie Barbour, Andrew Beggs, Pradeep Bhandari, Daniel Blakeway, Matthew Brookes, James Brown, Matthew Brown, Germaine Caldwell, Samuel Clokie, Ben Colleypriest, Abby Conlin, Shanika de Silva, John de Caestecker, Jonathan Deeks, Anjan Dhar, Mark Dilworth, Edward Fogden, Stephen Foley, Deb GhoshLeonie Grellier, Ailsa Hart, Syed Samiul Hoque, Marietta Iacucci, Tariq Iqbal, Jonathan James, Mark Jarvis, Anthoor Jayaprakash, Satish Keshav, Laura Magill, Glenn Matthews, Joel Mawdsley, Simon McLaughlin, Samir Mehta, Kevin Monahan, Dion Morton, Senthil Murugesan, Miles Parkes, Valerie Pestinger, Chris Probert, Arvind Ramadas, Alessandro Rettino, Shaji Sebastian, Naveen Sharma, Michael Griffiths, Joanne Stockton, Venkat Subramanian, Nigel Suggett, Philippe Taniere, Julian Teare, Ajay M Verma, Yvonne Wallis

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Abstract

Background: Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection.

Objectives: To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme.

Design: Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later.

Setting: Thirty-one UK hospitals.

Participants: Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis.

Interventions: An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy.

Main outcome: Identifying ulcerative colitis patients with neoplasia.

Results: Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09).

Limitations: Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed.

Conclusions: Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes.

Trial registration: Current Controlled Trials ISRCTN81826545.

Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.

Original language	English
Pages (from-to)	1-87
Number of pages	87
Journal	Efficacy and Mechanism Evaluation
Volume	8
Issue number	1
DOIs	https://doi.org/10.3310/eme08010
Publication status	Published - 31 Jan 2021

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Awasthi, A., Barbour, J., Beggs, A., Bhandari, P., Blakeway, D., Brookes, M., Brown, J., Brown, M., Caldwell, G., Clokie, S., Colleypriest, B., Conlin, A., Silva, S. D., Caestecker, J. D., Deeks, J., Dhar, A., Dilworth, M., Fogden, E., Foley, S., ... Wallis, Y. (2021). Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study. Efficacy and Mechanism Evaluation, 8(1), 1-87. https://doi.org/10.3310/eme08010

@article{39765786b607458285fdab9a4a023b40,

title = "Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study",

abstract = "Background: Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection.Objectives: To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme.Design: Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later.Setting: Thirty-one UK hospitals.Participants: Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis.Interventions: An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy.Main outcome: Identifying ulcerative colitis patients with neoplasia.Results: Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09).Limitations: Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed.Conclusions: Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes.Trial registration: Current Controlled Trials ISRCTN81826545.Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.",

author = "Ashish Awasthi and Jamie Barbour and Andrew Beggs and Pradeep Bhandari and Daniel Blakeway and Matthew Brookes and James Brown and Matthew Brown and Germaine Caldwell and Samuel Clokie and Ben Colleypriest and Abby Conlin and Silva, {Shanika de} and Caestecker, {John de} and Jonathan Deeks and Anjan Dhar and Mark Dilworth and Edward Fogden and Stephen Foley and Deb Ghosh and Leonie Grellier and Ailsa Hart and Hoque, {Syed Samiul} and Marietta Iacucci and Tariq Iqbal and Jonathan James and Mark Jarvis and Anthoor Jayaprakash and Satish Keshav and Laura Magill and Glenn Matthews and Joel Mawdsley and Simon McLaughlin and Samir Mehta and Kevin Monahan and Dion Morton and Senthil Murugesan and Miles Parkes and Valerie Pestinger and Chris Probert and Arvind Ramadas and Alessandro Rettino and Shaji Sebastian and Naveen Sharma and Michael Griffiths and Joanne Stockton and Venkat Subramanian and Nigel Suggett and Philippe Taniere and Julian Teare and Verma, {Ajay M} and Yvonne Wallis",

year = "2021",

month = jan,

day = "31",

doi = "10.3310/eme08010",

language = "English",

volume = "8",

pages = "1--87",

journal = "Efficacy and Mechanism Evaluation",

issn = "2050-4365",

publisher = "Prepress Projects Ltd",

number = "1",

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Awasthi, A, Barbour, J, Beggs, A, Bhandari, P, Blakeway, D, Brookes, M, Brown, J, Brown, M, Caldwell, G, Clokie, S, Colleypriest, B, Conlin, A, Silva, SD, Caestecker, JD, Deeks, J, Dhar, A, Dilworth, M, Fogden, E, Foley, S, Ghosh, D, Grellier, L, Hart, A, Hoque, SS, Iacucci, M , Iqbal, T, James, J, Jarvis, M, Jayaprakash, A, Keshav, S, Magill, L, Matthews, G, Mawdsley, J, McLaughlin, S, Mehta, S, Monahan, K, Morton, D, Murugesan, S, Parkes, M, Pestinger, V, Probert, C, Ramadas, A, Rettino, A, Sebastian, S, Sharma, N, Griffiths, M, Stockton, J, Subramanian, V, Suggett, N, Taniere, P, Teare, J, Verma, AM & Wallis, Y 2021, 'Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study', Efficacy and Mechanism Evaluation, vol. 8, no. 1, pp. 1-87. https://doi.org/10.3310/eme08010

TY - JOUR

T1 - Enhanced neoplasia detection in chronic ulcerative colitis

T2 - the ENDCaP-C diagnostic accuracy study

AU - Awasthi, Ashish

AU - Barbour, Jamie

AU - Beggs, Andrew

AU - Bhandari, Pradeep

AU - Blakeway, Daniel

AU - Brookes, Matthew

AU - Brown, James

AU - Brown, Matthew

AU - Caldwell, Germaine

AU - Clokie, Samuel

AU - Colleypriest, Ben

AU - Conlin, Abby

AU - Silva, Shanika de

AU - Caestecker, John de

AU - Deeks, Jonathan

AU - Dhar, Anjan

AU - Dilworth, Mark

AU - Fogden, Edward

AU - Foley, Stephen

AU - Ghosh, Deb

AU - Grellier, Leonie

AU - Hart, Ailsa

AU - Hoque, Syed Samiul

AU - Iacucci, Marietta

AU - Iqbal, Tariq

AU - James, Jonathan

AU - Jarvis, Mark

AU - Jayaprakash, Anthoor

AU - Keshav, Satish

AU - Magill, Laura

AU - Matthews, Glenn

AU - Mawdsley, Joel

AU - McLaughlin, Simon

AU - Mehta, Samir

AU - Monahan, Kevin

AU - Morton, Dion

AU - Murugesan, Senthil

AU - Parkes, Miles

AU - Pestinger, Valerie

AU - Probert, Chris

AU - Ramadas, Arvind

AU - Rettino, Alessandro

AU - Sebastian, Shaji

AU - Sharma, Naveen

AU - Griffiths, Michael

AU - Stockton, Joanne

AU - Subramanian, Venkat

AU - Suggett, Nigel

AU - Taniere, Philippe

AU - Teare, Julian

AU - Verma, Ajay M

AU - Wallis, Yvonne

PY - 2021/1/31

Y1 - 2021/1/31

N2 - Background: Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection.Objectives: To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme.Design: Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later.Setting: Thirty-one UK hospitals.Participants: Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis.Interventions: An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy.Main outcome: Identifying ulcerative colitis patients with neoplasia.Results: Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09).Limitations: Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed.Conclusions: Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes.Trial registration: Current Controlled Trials ISRCTN81826545.Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.

AB - Background: Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection.Objectives: To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme.Design: Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later.Setting: Thirty-one UK hospitals.Participants: Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis.Interventions: An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy.Main outcome: Identifying ulcerative colitis patients with neoplasia.Results: Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09).Limitations: Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed.Conclusions: Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes.Trial registration: Current Controlled Trials ISRCTN81826545.Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.

U2 - 10.3310/eme08010

DO - 10.3310/eme08010

M3 - Article

SN - 2050-4365

VL - 8

SP - 1

EP - 87

JO - Efficacy and Mechanism Evaluation

JF - Efficacy and Mechanism Evaluation

IS - 1

ER -

Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study

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