Early Detection of Ovarian Cancer Through Epigenetic Factors in the WHI

通过 WHI 中的表观遗传因素早期发现卵巢癌

基本信息

批准号：
9240606
负责人：
JEANINE M. GENKINGER
金额：
$ 57.23万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-08 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240606
关键词：
Aberrant DNA Methylation Address BRCA1 gene Biological Markers Blood Blood specimen CA-125 Antigen Cancer Etiology Cancer Survivor Cessation of life Clear Cell Clinical Clinical Research Collection Colorectal Cancer Complex DNA DNA Methylation Data Detection Diagnosis Discrimination Disease Early Diagnosis Early identification Epidemiology Epigenetic Process Etiology Event Family Future Genes Genetic Genetic Predisposition to Disease Genomic DNA Genomics Goals High Risk Woman Histology Hormonal Incidence Individual Literature Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Measurement Measures Methods Methylation Modality Modeling Morbidity - disease rate Normal tissue morphology Operative Surgical Procedures Outcome Performance Plasma Population Prevention Primary Prevention Prospective Studies Prospective cohort Research Risk Risk Assessment Risk Marker Risk stratification Screening for Ovarian Cancer Secondary Prevention Serous Survival Rate Targeted Resequencing The Cancer Genome Atlas Tissues Validation Woman Women&apos s Health base biomarker identification biomarker panel breast cancer family registry cancer diagnosis cancer risk carcinogenesis carcinogenicity case control cell free DNA clinically relevant design early detection biomarkers epidemiologic data epidemiology study high risk improved lifestyle factors malignant breast neoplasm methylation biomarker methylation pattern mortality multidisciplinary novel novel marker prospective public health relevance screening tool tumor

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the 5th leading cause of cancer death among US women; 62% of cases are diagnosed at advanced stages in which only 27% survive past 5 years. Yet, when ovarian cancer is detected at the localized stage (15% of cases), the 5 year survival rate is 94%. As survival is drastically improved if diagnosed early, methods to improve early detection through enhanced risk assessment, leading to better targeted primary prevention and screening are critical. The two validated risk assessment models from Rosner and Pfeiffer identify women at higher risk for ovarian cancer, but only have modest discriminatory power. Currently, no effective screening modality exists for ovarian cancer. Previous approaches for screening using single markers such as CA-125 in average risk populations have been unsuccessful, and led to many false positive results. Identifying novel panels of markers important to early carcinogenesis is key; epigenetic events (DNA methylation) are noted to occur early in carcinogenesis and reflect environmental insults and genetic vulnerability. Measurement of DNA methylation in cell free DNA has shown promise for early detection and screening for other cancers. Emerging evidence has shown that DNA methylation of select genes measured in tissue and plasma results in sensitivities >75% for detecting ovarian cancer. Yet, all evidence for ovarian cancer comes from small cross-sectional or retrospective clinical studies with no or limited epidemiologic data, raising concerns about temporality and confounding. We propose to replicate and build upon these promising findings by identifying a panel of DNA methylation markers that can detect ovarian cancer early. Using the Women's Health Initiative (WHI), one of the largest prospective studies in the US for women's health, we will verify differences in DNA methylation of 96 key genes (discovered by The Cancer Genome Atlas (TCGA)) measured in tumor vs. adjacent non tumor tissue using high throughput targeted resequencing. From these 96 TCGA genes, we will identify the top 10 genes that are differentially methylated by histology (npairs=200; Aim 1). In a nested case control (ncases=610; Aim 2), we will examine if DNA methylation of these top 10 genes measured in plasma are predictors of ovarian cancer risk years prior to cancer diagnosis. In Aim 3, we will evaluate the overall performance of DNA methylation markers to enhance existing ovarian cancer risk models in terms of accuracy, discrimination and false positives (n=161,808 women). We will validate our findings in an independent prospective cohort, the Breast Cancer Family Registry ((BCFR); n=11,950 families; ncases=164; Aim 4). The WHI and BCFR are ideal studies to conduct these aims; both have collected biospecimens and detailed epidemiologic data. We will employ a novel two-tiered approach for early detection of ovarian cancer that examines promising biomarkers (secondary prevention) across the spectrum of ovarian cancer risk (primary prevention). Our goal is through accurate identification of high risk individuals and reliable markers of early detection, we will reduce false positives, morbidity and mortality from ovarian cancer.

描述（由申请人提供）：卵巢癌是美国妇女癌症死亡的第五个主要原因； 62％的病例是在高级阶段诊断出的，在过去的5年中，只有27％的病例幸存下来。但是，当在局部阶段检测到卵巢癌（占病例的15％）时，5年的存活率为94％。由于早期诊断出生存率会大大提高，因此通过增强风险评估来改善早期检测的方法，导致靶向更好的初级预防和筛查至关重要。罗斯纳（Rosner）和菲佛（Pfeiffer）的两个验证的风险评估模型确定了卵巢癌风险较高的女性，但只有适度的歧视能力。目前，卵巢癌尚无有效的筛查方式。先前使用单个标记（例如平均风险种群）筛查的方法未成功，并导致了许多假阳性结果。识别对早期癌变重要的标志物的新颖面板是关键。表观遗传事件（DNA甲基化）在癌变早期发生，并反映了环境侮辱和遗传脆弱性。无细胞DNA中DNA甲基化的测量已显示出对其他癌症的早期检测和筛查的希望。新兴的证据表明，在组织和血浆中测得的精选基因的DNA甲基化导致敏感性> 75％，用于检测卵巢癌。然而，所有证据的卵巢癌证据都来自没有或有限的流行病学数据的小型横断面或回顾性临床研究，从而引起了人们对时间性和混杂性的关注。我们建议通过鉴定一组可以尽早检测到卵巢癌的DNA甲基化标记来复制和建立这些有希望的发现。使用妇女健康计划（WHI），这是美国妇女健康的最大前瞻性研究之一，我们将验证96个关键基因的DNA甲基化差异（由癌症基因组图集（TCGA）发现，在肿瘤邻近与邻近的甲基化差异非肿瘤组织使用高吞吐量的靶向重新配置。从这96个TCGA基因中，我们将确定由组织学差异化甲基化的前10个基因（Npairs = 200； AIM 1）。在嵌套的病例对照（NCases = 610; AIM 2）中，我们将检查这些在血浆中测得的十大基因的DNA甲基化是否是癌症诊断前卵巢癌风险年份的预测指标。在AIM 3中，我们将评估DNA甲基化标记的整体性能，以在准确性，歧视和假阳性方面增强现有的卵巢癌风险模型（n = 161,808女性）。我们将在独立的前瞻性队列中验证我们的发现，即乳腺癌家族登记册（（BCFR）； n = 11,950个家庭； ncases = 164; aim 4）。 WHI和BCFR是进行这些目标的理想研究。两者都收集了生物测量和详细的流行病学数据。我们将采用一种新型的两层方法来早日检测卵巢癌，该方法检查了卵巢癌风险（主要预防）的有希望的生物标志物（二级预防）。我们的目标是通过准确鉴定高风险个体和早期发现的可靠标记，我们将减少卵巢癌的假阳性，发病率和死亡率。