Multi-site Gastrointestinal Cancer Detection by Stool DNA Methylation

通过粪便 DNA 甲基化进行多部位胃肠癌检测

• 批准号: 10443018
• 负责人: John Kisiel
• 金额: $ 39.54万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443018
• 关键词: Address; Adenocarcinoma; Alleles; Anatomy; Archives; Barrett Esophagus; Biological Assay; Biological Markers; Body mass index; Buffers; Cancer Control; Cancer Detection; Case/Control Studies; Categories; Cessation of life; Classification; Colon; Colonoscopy; Colorectal; Colorectal Cancer; Confidence Intervals; DNA; DNA Methylation; Data; Detection; Development; Diagnostic; Duct (organ) structure; Early Diagnosis; Esophagus; Evaluation; FDA approved; Feces; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Incidence; Inflammatory Bowel Diseases; Knowledge; Laboratories; Lead; Life; Literature; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Measurement; Measures; Methylation; Mission; Modeling; Modification; Molecular; Non-Malignant; Non-Steroidal Anti-Inflammatory Agents; Organ; Pancreas; Patients; Phase; Positive Test Result; Prevalence; Race; Recording of previous events; Reproducibility; Sampling; Screening for cancer; Sensitivity and Specificity; Signal Transduction; Site; Specificity; Technology; Testing; Time; Tissues; Tobacco; Training; United States National Institutes of Health; Validation; age effect; alcohol exposure; body system; burden of illness; cancer site; chronic pancreatitis; cohort; colon cancer patients; colorectal cancer screening; cost effective; cost efficient; design; disorder control; gastrointestinal; improved; improved outcome; molecular sequence database; next generation sequencing; novel; pancreatic cancer patients; performance tests; preservation; public health relevance; research clinical testing; screening; sex; stool sample; upper gastrointestinal cancer; validation studies

PROJECT SUMMARY/ABSTRACT: Gastrointestinal (GI) malignancies lead cancer deaths worldwide, killing ~3 million annually. In the U.S., only colorectal cancers (CRC) are screened. Other GI cancers are not screened due to lack of accurate tests or because prevalence is deemed too low for cost-effective screening. Consequently, most patients with GI cancers present at late-stage and cure rates remain abysmally low. Effective early detection is desperately needed to improve outcomes. Our group was central in development and validation of the FDA-approved multi- target stool DNA test for CRC screening. We have begun to expand this approach, showing feasibility to detect supra-colonic GI cancers by stool DNA testing. However, it is critical for a non-invasive molecular test to localize the site of a primary cancer (“site-prediction”). Key preliminary data suggest that this may now be possible. First, we have completed rigorous next-generation sequencing to identify differentially methylated regions (DMRs) which appear highly discriminant for universal and site-specific detection of GI cancers. Second, we prioritized these DMRs by strict filtering criteria and performed a confirmatory study with statistical cross-validation on an independent set of CRC, gastroesophageal and pancreatico-biliary cancer, and normal control tissues. This showed that a panel of 8 selected DMRs could distinguish cancer from normal (95% accuracy) and assign organ site (94-95% accuracy for each category) with overall site-prediction accuracy of 88%. Third, these findings have been confirmed with novel DMRs assayed from stool specimens obtained from CRC and pancreatic cancer patients and normal controls (30, each). Using a 2-stage analysis, cancers were distinguished from controls at 90% specificity in the first stage. At stage 2, the markers accurately classified CRCs from pancreatic cancers with 90% accuracy. It is now our central hypothesis that luminal and ductal adenocarcinomas can be detected and localized by stool assay of universal and site-specific DMRs. This raises 3 key questions: 1) will stool assay of our novel DMRs show the high overall cancer sensitivity and the site-prediction we have seen in preliminary data; 2) will the DMRs be specific for cancer across a wide patient demographic spectrum and in the setting of non-malignant GI diseases; and 3) can sensitivity and specificity be improved by novel assay technology? These will be addressed in the following parallel, integrated, but independent specific aims: 1) Assess panel sensitivity and site-prediction accuracy in stool specimens for adenocarcinoma at esophageal, pancreatic and colorectal sites; 2) Confirm and evaluate DMR specificity in stool; and 3) Optimize novel assay conditions and marker selection for cancer detection and site-prediction at esophageal, pancreatic and colorectal sites. With our team’s strong track record, extensive stool archive, and unique access to a state-of-the art assay platform, we expect to demonstrate in a cost-efficient manner the feasibility of a novel DMR panel for the detection and site prediction of specific GI adenocarcinomas. Results will inform designs of future studies ranging from large- scale case-control studies (phase 2) on early-stage cancer and pre-cursors to pivotal cohort validation (phase 4) of a non-invasive multi-GI cancer screening test. The potential impacts on cancer control are far-reaching.

项目摘要/摘要： 胃肠道（GI）恶性肿瘤导致全球癌症死亡，每年造成约300万人。在美国，仅 筛选结直肠癌（CRC）。由于缺乏准确的测试或因为 患病率被认为太低，无法进行具有成本效益的筛查。因此，大多数胃肠道癌患者存在于 后期和治疗率仍然较低。迫切需要有效的早期检测来改进 结果。我们的小组在开发和验证FDA批准的多目标粪便DNA测试方面是中心的 用于CRC筛选。我们已经开始扩展这种方法，显示出可行的检测上gi的可行性 通过粪便DNA测试。但是，对于非侵入性分子测试而言，将原发性癌症的部位定位至关重要 （“站点预测”）。关键的初步数据表明这可能是可能的。首先，我们已经完成 严格的下一代测序以识别出不同的甲基化区域（DMR），这似乎很高 gi癌的通用和特定地点检测的判别。其次，我们严格将这些DMR优先考虑 过滤标准，并在独立的CRC集中进行了统计交叉验证的确认研究 胃食管和胰腺癌癌以及正常对照组织。这表明一个面板8 选定的DMR可以将癌症与正常（95％精度）和器官位点区分开（94-95％的精度 每个类别）的整体场地预测准确性为88％。第三，这些发现已被小说证实 从CRC和胰腺癌患者和正常对照组中获得的粪便标本分配的DMR（30，30， 每个）。使用2阶段的分析，在第一阶段将癌症与90％特异性的对照区分开。 第2阶段，标记物准确地从胰腺癌中准确地分类了CRC，精度为90％。现在是我们的中央 假设可以通过通用粪便测定和 特定地点的DMR。这提出了3个关键问题：1）将对我们的小说DMR的粪便评估显示出很高的总体 癌症敏感性和我们在初步数据中看到的场地预测； 2）DMR会针对 在广泛的患者人口谱以及非恶性GI疾病的情况下进行癌症； 3）可以 新颖的测定技术可以提高敏感性和特异性？这些将在以下内容中解决 平行，集成但独立的特定目的：1）评估面板灵敏度和场地预测精度 食管，胰腺和结直肠部位的腺癌标本； 2）确认和 评估粪便中的DMR特异性； 3）优化癌症的新型测定条件和标志物选择 食管，胰腺和结直肠部位的检测和现场预测。凭借我们团队的良好轨道 记录，广泛的凳子档案以及对最先进的测定平台的独特访问，我们希望证明 以成本效益 腺癌。结果将为未来研究的设计提供信息，从大型病例对照研究 （第2阶段）关于非侵入性多GI的早期癌症和前癌前验证者（第4阶段） 癌症筛查测试。对癌症控制的潜在影响是深远的。