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

Research output: Contribution to journalArticlepeer-review

Authors

  • Ashish Awasthi
  • Jamie Barbour
  • Pradeep Bhandari
  • Matthew Brookes
  • James Brown
  • Matthew Brown
  • Samuel Clokie
  • Ben Colleypriest
  • Abby Conlin
  • Shanika de Silva
  • John de Caestecker
  • Anjan Dhar
  • Mark Dilworth
  • Edward Fogden
  • Stephen Foley
  • Deb Ghosh
  • Leonie Grellier
  • Ailsa Hart
  • Syed Samiul Hoque
  • 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 Somani
  • Chris Probert
  • Arvind Ramadas
  • Alessandro Rettino
  • Shaji Sebastian
  • Naveen Sharma
  • Michael Griffiths
  • Jo Stockton
  • Venkat Subramanian
  • Nigel Suggett
  • Philippe Taniere
  • Julian Teare
  • Ajay M Verma
  • Yvonne Wallis

External organisations

  • University of Birmingham

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.

Details

Original languageEnglish
Pages (from-to)1-87
Number of pages87
JournalEfficacy and Mechanism Evaluation
Volume8
Issue number1
Publication statusPublished - 31 Jan 2021

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