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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要：胃肠道 (GI) 恶性肿瘤导致全球癌症死亡，仅在美国每年就有约 300 万人死亡。结直肠癌 (CRC) 得到筛查由于缺乏准确的检测或其他胃肠道癌症未得到筛查。由于患病率被认为太低，无法进行具有成本效益的筛查，因此大多数患有胃肠道疾病的患者。癌症已处于晚期，有效的早期检测仍然非常低。我们的团队是 FDA 批准的多重治疗的开发和验证的核心。用于 CRC 筛查的目标粪便 DNA 检测我们已经开始扩展这种方法，显示出检测的可行性。通过粪便 DNA 检测诊断结肠上消化道癌症然而，非侵入性分子检测至关重要。定位原发癌症的部位（“部位预测”）。关键初步数据表明，这可能是。首先，我们已经完成了严格的下一代测序，以识别差异甲基化。区域（DMR）对于胃肠道癌症的普遍和位点特异性检测具有高度区分性。其次，我们通过严格的过滤标准对这些 DMR 进行优先排序，并进行了统计验证研究对一组独立的 CRC、胃食管癌、胰胆癌和正常人进行交叉验证这表明一组 8 个选定的 DMR 可以区分癌症和正常组织（95%）。准确度）并分配器官部位（每个类别的准确度为 94-95%），总体部位预测准确度为这些发现已通过从粪便样本中检测的新型 DMR 得到证实来自 CRC 和胰腺癌患者和正常对照（各 30 个），使用两阶段分析，癌症。在第一阶段，标记物以 90% 的特异性与对照区分开来。在第二阶段，标记物准确无误。将 CRC 与胰腺癌分类，准确率达 90%。第三，88%。现在我们的中心假设是，管腔和导管腺癌可以通过粪便检测通用和位点特异性 DMR 来检测和定位。这就提出了 3 个关键问题：1) 我们的新型 DMR 的粪便检测是否会显示出较高的总体癌症敏感性以及我们在初步数据中看到的位点预测；2）DMR 是否针对癌症具有特异性？广泛的患者人口统计范围和非恶性胃肠道疾病的情况；3) 可以敏感性和通过新的检测技术可以提高特异性吗？这些将在以下并行中解决，综合但独立的具体目标：1）评估面板敏感性和站点预测准确性食管、胰腺和结直肠部位腺癌的粪便标本；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物选择与我们团队一起在食管、胰腺和结直肠部位进行癌症检测和部位预测。我们期望良好的记录、广泛的粪便档案以及对最先进检测平台的独特访问以经济高效的方式展示新型 DMR 面板用于检测和定位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。针对早期癌症和关键队列验证前体的规模病例对照研究（第二阶段） 4）非侵入性多胃肠道癌症筛查测试对癌症控制的潜在影响是深远的。