Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study
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. Detecti...
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| Language: | English |
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NIHR Journals Library
2021-01-01
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| Series: | Efficacy and Mechanism Evaluation |
| Subjects: | |
| Online Access: | https://doi.org/10.3310/eme08010 |
| _version_ | 1818060969590390784 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ashish Awasthi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T13:40:52Z |
| format | Article |
| id | doaj.art-0dc01abacbe24fca9990d9312a441d4a |
| institution | Directory Open Access Journal |
| issn | 2050-4365 2050-4373 |
| language | English |
| last_indexed | 2024-12-10T13:40:52Z |
| publishDate | 2021-01-01 |
| publisher | NIHR Journals Library |
| record_format | Article |
| series | Efficacy and Mechanism Evaluation |
| spelling | doaj.art-0dc01abacbe24fca9990d9312a441d4a2022-12-22T01:46:41ZengNIHR Journals LibraryEfficacy and Mechanism Evaluation2050-43652050-43732021-01-018110.3310/eme08010NIHR127442Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy studyAshish Awasthi0Jamie Barbour1Andrew Beggs2Pradeep Bhandari3Daniel Blakeway4Matthew Brookes5James Brown6Matthew Brown7Germaine Caldwell8Samuel Clokie9Ben Colleypriest10Abby Conlin11Shanika de Silva12John de Caestecker13Jonathan Deeks14Anjan Dhar15Mark Dilworth16Edward Fogden17Stephen Foley18Deb Ghosh19Leonie Grellier20Ailsa Hart21Syed Samiul Hoque22Marietta Iacucci23Tariq Iqbal24Jonathan James25Mark Jarvis26Anthoor Jayaprakash27Satish Keshav28Laura Magill29Glenn Matthews30Joel Mawdsley31Simon McLaughlin32Samir Mehta33Kevin Monahan34Dion Morton35Senthil Murugesan36Miles Parkes37Valerie Pestinger38Chris Probert39Arvind Ramadas40Alessandro Rettino41Shaji Sebastian42Naveen Sharma43Michael Griffiths44Joanne Stockton45Venkat Subramanian46Nigel Suggett47Philippe Taniere48Julian Teare49Ajay M Verma50Yvonne Wallis51Department of Gastroenterology, Manor Hospital, Walsall, UKDepartment of Inflammatory Bowel Disease, Queen Elizabeth Hospital, Gateshead, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, Queen Alexandra Hospital Portsmouth, Portsmouth, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, New Cross Hospital, Wolverhampton, UKBirmingham Clinical Trials Unit, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, Basingstoke and North Hampshire Hospital, Basingstoke, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKWest Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UKDepartment of Gastroenterology, Royal United Hospital Bath, Bath, UKDepartment of Gastroenterology, Salford Royal Hospital, Manchester, UKDepartment of Gastroenterology, Russells Hall Hospital, Dudley, UKDepartment of Gastroenterology, University Hospitals Leicester, Leicester, UKBirmingham Clinical Trials Unit, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, Directorate of Medicine and Acute Care, County Durham and Darlington NHS Foundation Trust, Durham, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, City Hospital, Birmingham, UKDepartment of Gastroenterology, King’s Mill Hospital, Sutton-in-Ashfield, UKDepartment of Gastroenterology, Princess Alexandra Hospital, Harlow, UKDepartment of Gastroenterology, Newport, Isle of Wight, UKDepartment of Gastroenterology and Inflammatory Bowel Unit, St Mark’s Hospital and Academic Institute, Middlesex, UKDepartment of Gastroenterology, Whipps Cross Hospital, London, UKUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, Basildon and Thurrock University Hospital, Essex, UKDepartment of Gastroenterology, North Tyneside General Hospital, North Shields, UKGastroenterology Unit, John Radcliffe Hospital, Oxford, UKBirmingham Clinical Trials Unit, University of Birmingham, Birmingham, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, West Middlesex University Hospital, Middlesex, UKDepartment of Gastroenterology, Royal Bournemouth Hospital, Bournemouth, UKBirmingham Clinical Trials Unit, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, West Middlesex University Hospital, Middlesex, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, Blackpool Victoria Hospital, Blackpool, UKDepartment of Gastroenterology, Addenbrookes Hospital, Cambridge, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, Institute for Translational Medicine, Royal Liverpool and Broadgreen University Hospitals, Liverpool, UKDepartment of Gastroenterology, James Cook University Hospital, Middlesbrough, UKWest Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UKDepartment of Gastroenterology, Hull Royal Infirmary, Hull, UKUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UKWest Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UKInstitute of Cancer and Genomic Science, University of Birmingham, Birmingham, UKDepartment of Gastroenterology, St James’s University Hospital, Leeds, UKUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UKUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UKDepartment of Gastroenterology, St Mary’s Hospital, London, UKDepartment of Gastroenterology, Kettering General Hospital, Kettering, UKWest Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UKBackground: 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.https://doi.org/10.3310/eme08010ulcerative colitischronic colitiscancerdysplasiapredictive biomarkerdnamethylationsurveillancecolonoscopy |
| spellingShingle | 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 Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study Efficacy and Mechanism Evaluation ulcerative colitis chronic colitis cancer dysplasia predictive biomarker dna methylation surveillance colonoscopy |
| title | Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study |
| title_full | Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study |
| title_fullStr | Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study |
| title_full_unstemmed | Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study |
| title_short | Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study |
| title_sort | enhanced neoplasia detection in chronic ulcerative colitis the endcap c diagnostic accuracy study |
| topic | ulcerative colitis chronic colitis cancer dysplasia predictive biomarker dna methylation surveillance colonoscopy |
| url | https://doi.org/10.3310/eme08010 |
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