Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study-猫眼课题宝

DOI：

10.3310/eme08010

发表时间：

2021

期刊：

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作者：

A. Awasthi;J. Barbour;A. Beggs;P. Bhandari;D. Blakeway;M. Brookes;James B. Brown;M. Brown;G. Caldwell;S. Clokie;B. Colleypriest;A. Conlin;S. Silva;J. D. Caestecker;J. Deeks;A. Dhar;M. Dilworth;E. Fogden;S. Foley;Debanjan Ghosh;L. Grellier;A. Hart;S. Hoque;M. Iacucci;T. Iqbal;J. James;M. Jarvis;Anthoor Jayaprakash;S. Keshav;L. Magill;G. Matthews;J. Mawdsley;S. McLaughlin;S. Mehta;K. Monahan;D. Morton;S. Murugesan;M. Parkes;V. Pestinger;C. Probert;A. Ramadas;A. Rettino;S. Sebastian;Naveen Sharma;M. Griffiths;Joanne Stockton;V. Subramanian;N. Suggett;P. Tanière;J. Teare;A. Verma;Y. Wallis

背景慢性溃疡性结肠炎是一种大肠炎性疾病，随着时间的推移，结肠直肠癌的风险增加，导致英国每年1000例结肠切除术。尽管有密集的结肠镜监测，50%的病例在检测之前进展为浸润性癌症。通过分析常规结肠镜活检发现早期（癌前）分子变化，应增加肿瘤检出率。目的建立溃疡性结肠炎患者早期肿瘤改变的DNA标记物。在NHS内开发用于高通量分析的DNA甲基化测试。在现有的结肠镜监测计划中前瞻性地评价该试验。设计模块1使用焦磷酸测序法分析了来自肿瘤和非肿瘤部位/患者的569份储存的活检组织，用于先前报告的与结肠炎相关肿瘤相关的启动子甲基化改变的11个基因。构建分类器以基于基因组合预测瘤形成。模块2将分析转化为NHS实验室，评估下一代测序以提高速度并降低成本。模块3在现有溃疡性结肠炎监测计划中的前瞻性诊断准确性研究中应用了分子分类器。在6-12个月后的分层患者样本中进行基线和参考结肠镜检查之间的比较。英国31家医院参与者慢性溃疡性结肠炎患者，无论是至少10年和广泛的疾病，或与原发性硬化性胆管炎。干预一种优化的DNA甲基化分类器在结肠镜检查期间进行的常规粘膜活检中进行测试。主要结果：鉴别溃疡性结肠炎患者的肿瘤。结果模块1选择了5个肿瘤特异性基因。肿瘤的最佳调整后的受试者工作特征曲线下面积为0.83（95%置信区间为0.79至0.88）。癌前病变的受试者工作特征曲线下面积较高，为0.88（95%置信区间为0.84 - 0.92）。背景粘膜的辨别力较差（接受者工作特征曲线下的最佳调整面积为0.68，95%置信区间为0.62至0.73）。由于所有基因的扩增率都很低，模块2无法开发出稳健的下一代测序测定法。在模块3中，818例患者接受了基线结肠镜检查。将甲基化检测（检测非肿瘤性粘膜）与肿瘤的病理学评估进行比较，显示诊断优势比为2.37（95%置信区间1.46至3.82; p = 0.0002）。异型增生的概率从检测前的11.1%增加到检测后的17.7%（95%置信区间为13.0%至23.2%），阳性甲基化结果表明肿瘤检测的附加值。为了确定单独结肠镜检查的附加值，在193例无肿瘤的患者中进行了第二次（参考）结肠镜检查。尽管该测试显示与原发性甲基化变化相关的肿瘤患者数量增加，但未能达到统计学显著性（诊断比值比3.93; 95%置信区间0.82至24.75; p = 0.09）。自ENDCaP-C问世以来，技术已经发展到允许进行全基因组或甲基化组检测。结论基于这项研究，不能推荐慢性溃疡性结肠炎患者进行甲基化检测。然而，随访该队列将揭示进一步的肿瘤变化，表明该测试是否可以识别未来肿瘤形成风险的人群，并为未来的监测计划提供信息。试验注册当前对照试验ISRCTN 81826545。资金该项目由医学研究理事会和国家健康研究所（NIHR）合作伙伴关系功效和机制评估计划资助，并将在功效和机制评估中全文发表;第8卷，第1号。请参阅NIHR期刊图书馆网站了解更多项目信息。

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.

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

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