Multi-site Gastrointestinal Cancer Detection by Stool DNA Methylation

通过粪便 DNA 甲基化检测多部位胃肠癌

• 批准号: 9904132
• 负责人: John Kisiel
• 金额: $ 40.47万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904132
• 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; Cholangiocarcinoma; Colonoscopy; Colorectal; Colorectal Adenocarcinoma; Colorectal Cancer; Confidence Intervals; DNA; DNA Methylation; Data; Detection; Development; Diagnostic; Duct (organ) structure; Early Diagnosis; Esophageal Adenocarcinoma; 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; Mission; Modeling; Modification; Molecular; Non-Malignant; Non-Steroidal Anti-Inflammatory Agents; Organ; Pancreas; Pancreatic Adenocarcinoma; 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; gastroesophageal cancer; 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 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. 88%. Third, 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 因为流行率太低，无法进行具有成本效益的筛查。因此，大多数GI患者 在晚期出现的癌症和治愈率仍然较低。有效的早期发现是拼命的 需要改善结果。我们的小组在开发和验证FDA批准的多重核心方面是核心 目标粪便DNA测试进行CRC筛选。我们已经开始扩展这种方法，显示出可行性 通过粪便DNA测试，超色gi癌。但是，对于非侵入性分子测试至关重要 定位原发性癌症的部位（“现场预测”）。关键初步数据表明这可能是 可能的。首先，我们已经完成了严格的下一代测序，以识别不同的甲基化 对于GI癌的通用和特定地点检测，似乎高度判别的区域（DMR）。 其次，我们通过严格的过滤标准将这些DMR优先考虑，并通过统计进行了确认研究 独立的CRC，胃食管和胰腺癌和正常的跨验验 控制组织。这表明，一个选定的DMR组的面板可以区分癌症和正常癌症（95％ 精度）和分配器官位点（每个类别的精度为94-95％），总体场地预测精度为 这些发现已通过从获得的粪便标本中分配的新型DMR证实 来自CRC和胰腺癌患者以及正常对照组（每个）。使用2阶段分析，癌症 在第一阶段的90％特异性方面与对照区分开。在第2阶段，标记准确 从胰腺癌中分类的CRC精度为90％。 88％。第三， 现在是我们的核心假设 可以通过通用和特异性DMR的粪便测定法检测并定位导管腺癌。 这提出了3个关键问题：1）将对我们新型DMR的粪便评估显示出高度的整体癌症敏感性 以及我们在初步数据中看到的场地预测； 2）DMR是否特定于A的癌症 广泛的患者人口统计学谱系和非恶性胃肠道疾病的情况； 3）可以敏感和 新颖的测定技术可以提高特异性吗？这些将在以下平行中解决 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）优化新的测定条件和标记选择 食管，胰腺和结直肠部位的癌症检测和现场预测。与我们的团队的 我们希望的 以经济高效的方式证明新型DMR面板用于检测和现场的可行性 特定胃肠道腺癌的预测。结果将为未来研究的设计提供信息，从大型研究 比例病例对照研究（第2阶段）关于早期癌症和关键队列验证前的前保车（相） 4）非侵入性多GI癌症筛查测试。对癌症控制的潜在影响是深远的。