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

• 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
• 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' 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

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）：卵巢癌是美国女性癌症死亡的第五大原因； 62% 的病例确诊时已处于晚期，其中只有 27% 的患者能活过 5 年。然而，当卵巢癌在局部阶段（15% 的病例）被发现时，5 年生存率为 94%。由于如果早期诊断，生存率会大大提高，因此通过加强风险评估来改善早期检测的方法，从而实现更有针对性的初级预防和筛查至关重要。罗斯纳和普法伊弗的两个经过验证的风险评估模型可以识别出患卵巢癌的较高风险的女性，但只有适度的歧视力。目前，尚无有效的卵巢癌筛查方式。以前使用 CA-125 等单一标记物对平均风险人群进行筛查的方法并不成功，并导致许多假阳性结果。识别对早期致癌重要的新标记物组是关键；表观遗传事件（DNA 甲基化）被发现发生在癌变早期，反映了环境损害和遗传脆弱性。游离 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。新的证据表明，在组织和血浆中测量的选定基因的 DNA 甲基化导致检测卵巢癌的灵敏度 >75%。然而，卵巢癌的所有证据都来自小型横断面或回顾性临床研究，没有或有限的流行病学数据，引发了人们对暂时性和混杂性的担忧。我们建议通过鉴定一组可以早期检测卵巢癌的 DNA 甲基化标记来复制和发展这些有希望的发现。利用女性健康倡议 (WHI)（美国最大的女性健康前瞻性研究之一），我们将使用高通量靶向重测序来验证肿瘤组织与邻近非肿瘤组织中测量的 96 个关键基因（由癌症基因组图谱 (TCGA) 发现）的 DNA 甲基化差异。从这 96 个 TCGA 基因中，我们将确定组织学差异甲基化的前 10 个基因（npairs=200；目标 1）。在嵌套病例对照（ncases=610；目标 2）中，我们将在癌症诊断前数年检查血浆中测量的前 10 个基因的 DNA 甲基化是否是卵巢癌风险的预测因子。在目标 3 中，我们将评估 DNA 甲基化标记的整体性能，以增强现有卵巢癌风险模型在准确性、区分度和假阳性方面的能力（n=161,808 名女性）。我们将在一个独立的前瞻性队列——乳腺癌家族登记处（(BCFR)；n=11,950 个家庭；ncases=164；目标 4）中验证我们的研究结果。 WHI 和 BCFR 是实现这些目标的理想研究；两者都收集了生物样本和详细的流行病学数据。我们将采用一种新颖的两级方法来早期检测卵巢癌，该方法检查整个卵巢癌风险（一级预防）中有希望的生物标志物（二级预防）。我们的目标是通过准确识别高风险个体和可靠的早期检测标志物，我们将减少卵巢癌的假阳性、发病率和死亡率。