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:
    9520603
  • 负责人:
  • 金额:
    $ 40.47万
  • 依托单位:
  • 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

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.
项目总结/摘要: 胃肠道(GI)恶性肿瘤导致全球癌症死亡,每年约有300万人死亡。在美国,只 结肠直肠癌(CRC)的筛查。其他胃肠道癌症由于缺乏准确的测试而没有筛查, 因为患病率被认为太低,无法进行成本效益高的筛查。因此,大多数GI患者 晚期癌症和治愈率仍然极低。有效的早期检测 需要改善结果。我们的团队是FDA批准的多功能药物的开发和验证的中心。 用于CRC筛查靶向粪便DNA测试。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检测检测结肠上胃肠道癌。然而,对于非侵入性分子检测来说, 定位原发性癌症的位点(“位点预测”)。关键的初步数据表明,这可能是现在 可能首先,我们已经完成了严格的下一代测序,以确定差异甲基化 区域(DMR),其对于GI癌症的通用和位点特异性检测表现出高度区分性。 其次,我们通过严格的筛选标准对这些DMR进行了优先排序,并进行了统计学验证性研究。 对CRC、胃食管癌和胰胆管癌以及正常人的独立集进行交叉验证 对照组织。这表明,一组8个选定的DMR可以区分癌症和正常(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 这些发现已被从粪便样本中检测的新型DMR所证实, 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 在第一阶段以90%的特异性与对照区分开。在第二阶段,标记物准确地 将CRC与胰腺癌进行分类的准确率为90%。 百分之八十八第三、 现在我们的中心假设是, 导管腺癌可以通过通用和位点特异性DMR的粪便测定来检测和定位。 这提出了3个关键问题:1)我们的新型DMR的粪便检测是否会显示出高的整体癌症敏感性 以及我们在初步数据中看到的位点预测; 2)DMR是否对整个癌症具有特异性? 广泛的患者人口统计学谱和非恶性GI疾病的背景下;和3)可以敏感性和 新型检测技术可以提高特异性吗?这些问题将在以下平行讨论, 综合的,但独立的具体目标:1)评估面板的敏感性和网站预测的准确性, 粪便标本用于食管、胰腺和结直肠部位的腺癌; 2)确认和 评价粪便中的DMR特异性;以及3)优化用于检测的新测定条件和标记物选择。 食道、胰腺和结直肠部位的癌症检测和部位预测。与我们团队的 强大的跟踪记录,广泛的粪便档案,以及对最先进的分析平台的独特访问,我们期望 以具有成本效益的方式证明新型DMR面板用于检测和现场的可行性 特异性GI腺癌的预测。结果将为未来研究的设计提供信息,从大型- 早期癌症的大规模病例对照研究(2期)和关键队列验证的前指标(2期 4)非侵入性多消化道癌症筛查测试对癌症控制的潜在影响是深远的。

项目成果

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John Kisiel其他文献

John Kisiel的其他文献

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{{ truncateString('John Kisiel', 18)}}的其他基金

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
  • 财政年份:
    2023
  • 资助金额:
    $ 40.47万
  • 项目类别:
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:
    10372020
  • 财政年份:
    2018
  • 资助金额:
    $ 40.47万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 40.47万
  • 项目类别:
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:
    10112835
  • 财政年份:
    2018
  • 资助金额:
    $ 40.47万
  • 项目类别:

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