Ovarian cancer risk stratification using circulating miRNAs to assess BRCAness

使用循环 miRNA 评估 BRCA 的卵巢癌风险分层

• 批准号: 10724815
• 负责人: Kevin Elias
• 金额: $ 17.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724815
• 关键词: American; Awareness; BARD1 gene; BRCA mutations; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Benefits and Risks; Biological; Biological Assay; Biological Markers; Blinded; Blood; Blood Tests; CHEK2 gene; Case/Control Studies; Cessation of life; Classification; Clinical Trials; Collection; Colon Carcinoma; Colorectal; DNA Repair; DNA Repair Gene; DNA Sequence Alteration; DNA Sequence Rearrangement; Data Set; Defect; Detection; Diagnosis; Endometrial Carcinoma; Enrollment; Epigenetic Process; Epithelial ovarian cancer; Event; Family Cancer History; Family history of; Future; General Population; Genes; Genetic Predisposition to Disease; Genetic Risk; Germ-Line Mutation; Guidelines; Hereditary Breast and Ovarian Cancer Syndrome; Individual; Institution; Lung; Malignant neoplasm of ovary; Measures; Methylation; MicroRNAs; Modeling; Mutate; Mutation; Operative Surgical Procedures; Ovarian; PALB2 gene; PTEN gene; Pathway interactions; Population; Prostate; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; RAD51C gene; Recording of previous events; Risk; Risk Assessment; Risk Factors; Risk Reduction; Salpingo-Oophorectomy; Sampling; Screening for Ovarian Cancer; Serum; Testing; Transvaginal Ultrasound; Triage; Woman; brca gene; cancer prevention; cancer risk; case control; circulating microRNA; comparison control; cost; design; early phase clinical trial; feasibility testing; gene repair; genetic information; genetic testing; high risk; high risk population; lifetime risk; malignant breast neoplasm; mutation carrier; mutational status; next generation sequencing; prevent; promoter; prospective; repaired; risk stratification; risk variant; sample collection; screening; study population; surveillance strategy; tool

Abstract Current strategies to prevent ovarian cancer deaths remain limited. Unlike breast and colon cancer, clinical trials for early detection of ovarian cancer have not been effective at reducing ovarian cancer deaths. In contrast, risk- reducing salpingo-oophorectomy for women with germline mutations in BRCA1/2 reduces the risk of ovarian cancer death by more than 95%. However, since current guidelines limit genetic testing to individuals with a personal or close family history of breast or ovarian cancer, only 10% of the estimated 1 million Americans with BRCA1/2 mutations are aware of their mutation status. We have shown that BRCA1/2 mutation carriers have a distinct serum microRNA (miRNA) profile which can be used to rapidly identify likely mutation carriers. In this proposal, we will use previously collected sample and datasets to discover the generalizability of this miRNA profile to other potentially high-risk groups. We will examine the serum miRNA profiles of both BRCA1/2 mutation carriers as well as carriers of mutations in other DNA repair genes and women with no discernible germline mutation but a strong family history of breast or ovarian cancer. Samples will be classified in terms of BRCAness, i.e., how closely they resemble BRCA1/2 mutation carriers versus healthy controls with average cancer risk. We will determine whether the BRCA1/2 miRNA profile is restricted to alterations in these specific genes or reflects a more general deficiency in DNA repair which could increase the risk of ovarian cancer. Independently, we will test whether the BRCAness miRNA profile is sufficient as an ovarian cancer risk triage tool, even in the absence of known genetic information. Using a case-control format, we will compare baseline miRNA profiles among a study population of average risk women who were enrolled in an ovarian cancer screening trial. We will calculate whether cases were more likely to have a BRCAness miRNA profile at study entry compared to controls. The final result of these studies will be to test whether serum miRNAs can serve as a biomarker to identify more women at risk for ovarian cancer who could benefit from risk-reduction strategies. This group can then be prioritized for future biologic studies and clinical trials.

摘要 目前预防卵巢癌死亡的策略仍然有限。与乳腺癌和结肠癌不同， 早期发现卵巢癌并不能有效降低卵巢癌死亡率。相反，风险- 减少BRCA 1/2生殖系突变妇女的输卵管卵巢切除术可降低卵巢癌的风险 癌症死亡率超过95%。然而，由于目前的指导方针限制基因检测的个人与 乳腺癌或卵巢癌的个人或密切的家族史，只有10%的估计100万美国人 BRCA 1/2突变知道他们的突变状态。我们已经证明BRCA 1/2突变携带者有一个 独特的血清microRNA（miRNA）谱，可用于快速识别可能的突变携带者。在这 我们将使用以前收集的样本和数据集来发现这种miRNA的普遍性 其他潜在的高风险群体。我们将检测BRCA 1/2突变和BRCA 1/2突变的血清miRNA谱， 携带者以及其他DNA修复基因突变的携带者和没有可辨别的生殖系的妇女 突变，但有乳腺癌或卵巢癌的家族史。样本将根据BRCAness进行分类， 也就是说，他们与BRCA 1/2突变携带者与具有平均癌症风险的健康对照者的相似程度如何。我们 将确定BRCA 1/2 miRNA谱是否仅限于这些特定基因的改变， 更普遍的DNA修复缺陷可能会增加卵巢癌的风险。独立地，我们将 测试BRCAness miRNA谱是否足以作为卵巢癌风险分类工具，即使在没有 已知的基因信息。使用病例对照的形式，我们将比较基线miRNA谱之间的差异。 研究对象为参加卵巢癌筛查试验的平均风险女性。我们将计算 与对照组相比，病例在研究进入时是否更可能具有BRCAness miRNA谱。的 这些研究的最终结果将是测试血清miRNAs是否可以作为生物标志物来识别更多的 有卵巢癌风险的妇女，他们可以从降低风险的策略中受益。然后，该组可以是 优先用于未来的生物学研究和临床试验。