Development of a low-cost epigenetic screening assay for Pap specimen-based detection of early-stage ovarian cancer in high-risk women

开发一种低成本表观遗传筛查方法,用于基于巴氏标本的高危女性早期卵巢癌检测

基本信息

  • 批准号:
    10317707
  • 负责人:
  • 金额:
    $ 44.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-15 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY With a 5-year survival rate of only 47%, high-grade serous carcinoma (HGSC) remains the most lethal of all types of ovarian cancer. This is a particular concern for women with familial histories or BRCA mutations, who exhibit 20 to 35-fold higher risk of developing HGSC in their lifetime. The high mortality of the disease is largely attributable to the fact that HGSC almost always remains undiagnosed until advanced stages when curative surgery is no longer feasible. Recently, numerous studies have demonstrated that most HGSCs likely originate in the fallopian tubes as precursor lesions called serous tubal intraepithelial carcinomas (STICs) that progress over a period of 6-7 years before rapidly metastasizing to the ovary and surrounding tissues. This suggests there exists a critical window of time in which STIC lesions and early-stage tumors might be detected so that tumor progression can be effectively intercepted before reaching an incurable stage. Recent studies have held out hope by showing that STIC and tumor cells are able to freely travel from the fallopian tubes to the cervix where they can be readily-detected in routinely-collected Pap specimens. Nonetheless, two notable challenges to this approach remain: (1) issues associated with the sensitivity and specificity of current biomarkers that undermine test performance and (2) a cost-effective diagnostic technology with sufficient sensitivity to detect exceedingly-rare copies of biomarkers from early-stage HGSC in complex samples such as Pap specimens. In the present proposal, we seek to address both of these challenges by developing a new type of HGSC screening assay called PapDREAM that is based on the sensitive, cost-effective detection of a novel set of epigenetic biomarkers that we have recently shown to be prevalently and specifically hypermethylated in both early, precursor (STIC) lesions and later-stage HGSC tumors. The PapDREAM assay will employ a unique, digital methylation analysis technique called µ-DREAMing (microfluidic Discrimination of Rare EpiAlleles by Melt) that provides a simple, but highly-effective means of detecting and quantifying rare, aberrantly- methylated DNA, even in challenging samples such as stool, liquid biopsies and Pap specimens. A user- friendly workflow based on common laboratory instrumentation will be developed to enable PapDREAM to be readily translated and performed in various research and clinical settings at a cost of only a few dollars per assay. Ultimately, the PapDREAM assay can be used alone or in combination with other assays to provide an ideal screening method for women at high risk for developing HGSC. We have assembled a multi-disciplinary team with complementary expertise in gynecologic pathology, assay development and DNA methylation bioinformatics to accomplish this goal by achieving the following aims: (1) Evaluate and prioritize methylation biomarkers to be included in the PapDREAM assay, (2) Incorporate µ- DREAMing assays into PapDREAM: a simple, multiplexed digital methylation assay for the detection of early- stage HGSC, and (3) Assess the clinical performance of the PapDREAM assay in Pap specimens.
项目总结 高级别浆液性癌(HGSC)的5年存活率只有47%,仍然是所有肿瘤中最致命的 卵巢癌的类型。这对有家族病史或BRCA突变的女性尤其令人担忧 在他们的一生中患HGSC的风险要高出20到35倍。这种疾病的高死亡率在很大程度上是 这是由于HGSC几乎总是在治愈的晚期才被诊断出来 手术不再可行。最近,大量的研究表明,大多数HGSC可能起源于 在输卵管中作为前驱病变的浆液性输卵管上皮内癌(STICs)进展 在迅速转移到卵巢和周围组织之前的6-7年内。这表明 存在一个关键的时间窗口,在该时间窗口中可以检测到STIC病变和早期肿瘤 在达到无法治愈的阶段之前,可以有效地阻止肿瘤的进展。最近的研究表明 通过展示STIC和肿瘤细胞能够从输卵管自由移动到宫颈,带来了希望 在那里,它们可以很容易地在常规收集的巴氏样本中被检测到。尽管如此,两个值得注意的挑战 这一方法仍然存在:(1)与当前生物标记物的敏感性和特异性相关的问题 破坏测试性能和(2)具有足够灵敏度的经济高效的诊断技术 非常罕见的来自早期HGSC的生物标记物在复杂样本中的拷贝,如巴氏样本。 在目前的提案中,我们试图通过开发一种新型的HGSC来应对这两个挑战 一种名为PapDREAM的筛选试验,其基础是对一组新的 我们最近发现的表观遗传生物标记物在这两种疾病中普遍存在并特别高甲基化 早期、前驱(STIC)病变和晚期HGSC肿瘤。PapDREAM检测将使用一种独特的, 数字甲基化分析技术,称为微梦(微流控鉴别稀有等位基因 熔化),提供了一种简单但高效的手段来检测和量化罕见的、异常的- DNA甲基化,即使在具有挑战性的样本中,如粪便、液体活组织检查和巴氏样本。用户- 将开发基于通用实验室仪器的友好工作流程,以使PapDREAM能够 易于翻译并在各种研究和临床环境中执行,每台仅需几美元 化验。最终,PapDREAM检测可以单独使用,也可以与其他检测结合使用,以提供 HGSC高危人群的理想筛查方法。 我们已经组建了一支多学科团队,在妇科病理学、化验方面具有互补的专业知识。 开发和DNA甲基化生物信息学通过实现以下目标来实现这一目标:(1) 评估和确定PapDREAM分析中要包括的甲基化生物标志物的优先顺序,(2)纳入µ- 梦想化验成PapDREAM:一种简单、多重的数字甲基化分析方法,用于检测早期- HGSC分期,以及(3)在巴氏标本中评估PapDREAM试验的临床表现。

项目成果

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Thomas Russell Pisanic II其他文献

Thomas Russell Pisanic II的其他文献

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{{ truncateString('Thomas Russell Pisanic II', 18)}}的其他基金

A low-cost, multiplexed digital high resolution melt platform for DNA methylation-based detection and identification of cancers in liquid biopsies
一种低成本、多重数字高分辨率熔解平台,用于液体活检中基于 DNA 甲基化的癌症检测和识别
  • 批准号:
    10697370
  • 财政年份:
    2022
  • 资助金额:
    $ 44.38万
  • 项目类别:
Development of a low-cost epigenetic screening assay for Pap specimen-based detection of early-stage ovarian cancer in high-risk women
开发一种低成本表观遗传筛查方法,用于基于巴氏标本的高危女性早期卵巢癌检测
  • 批准号:
    10428656
  • 财政年份:
    2021
  • 资助金额:
    $ 44.38万
  • 项目类别:
Development of a low-cost epigenetic screening assay for Pap specimen-based detection of early-stage ovarian cancer in high-risk women
开发一种低成本表观遗传筛查方法,用于基于巴氏标本的高危女性早期卵巢癌检测
  • 批准号:
    10678833
  • 财政年份:
    2021
  • 资助金额:
    $ 44.38万
  • 项目类别:

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