验证表观遗传标志物以识别结肠炎相关癌症：ENDCAP-C 研究模块 1 的结果。
Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study.
机构信息
Institute of Cancer & Genomic Science, University of Birmingham, UK.
Birmingham Clinical Trials Unit, University of Birmingham, UK.
出版信息
EBioMedicine. 2019 Jan;39:265-271. doi: 10.1016/j.ebiom.2018.11.034. Epub 2018 Nov 22.
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).
背景
溃疡性结肠炎（UC）引起的慢性炎症导致炎症结肠发生促瘤作用，与一般人群相比，UC 患者发生侵袭性恶性肿瘤的风险明显更高。尽管有监测方案，但仍有 50%的病例在发现肿瘤前进展为癌症。增强的慢性结肠炎中肿瘤检测和癌症预防（ENDCaP-C）试验是一项观察性多中心试验准确性研究，旨在确定分子标志物在提高对异型增生的检测中的作用。我们旨在通过回顾性队列中的验证和前瞻性队列中的预测模型，来验证先前确定的肿瘤发生生物标志物。
方法
对 6 家医疗中心的 35 例癌症患者、78 例异型增生患者和 343 例无 UC 相关性肿瘤患者的样本进行 11 个标志物（SFRP1、SFRP2、SRP4、SRP5、WIF1、TUBB6、SOX7、APC1A、APC2、MINT1、RUNX3）的亚硫酸氢盐焦磷酸测序的回顾性分析。在肿瘤和非肿瘤黏膜的背景下，建立用于 UC 相关性癌症/异型增生的预测模型。
结果
对于肿瘤黏膜，五标志物面板（SFRP2、SFRP4、WIF1、APC1A、APC2）在检测癌前和侵袭性肿瘤（AUC=0.83；95%CI：0.79，0.88）和异型增生（AUC=0.88；0.84，0.91）方面具有准确性。对于非肿瘤黏膜，四个标志物面板（APC1A、SFRP4、SFRP5、SOX7）在通过远处非肿瘤结肠黏膜的甲基化特征预测相关肠肿瘤方面具有适度的准确性（AUC=0.68；95%CI：0.62，0.73）。
结论
这种多重甲基化标志物面板在检测溃疡性结肠炎相关性异型增生和肿瘤方面具有准确性，目前正在一项前瞻性临床试验中进行验证。
资金
ENDCaP-C 研究由英国国家卫生研究院疗效和机制评估（EME）计划（11/100/29）资助。
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