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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的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，临床试验早期发现卵巢癌并不能有效减少卵巢癌死亡。相比之下，风险—— 减少 BRCA1/2 种系突变女性的输卵管卵巢切除术可降低卵巢癌风险癌症死亡95%以上。然而，由于目前的指导方针限制基因检测仅针对患有以下疾病的个体：个人或近亲有乳腺癌或卵巢癌病史，估计 100 万美国人中只有 10% 患有乳腺癌或卵巢癌 BRCA1/2 突变了解其突变状态。我们已经证明 BRCA1/2 突变携带者具有独特的血清 microRNA (miRNA) 谱可用于快速识别可能的突变携带者。在这个建议，我们将使用之前收集的样本和数据集来发现该 miRNA 的普遍性向其他潜在高风险群体介绍情况。我们将检查 BRCA1/2 突变的血清 miRNA 谱携带者以及其他 DNA 修复基因突变携带者以及没有明显种系的女性突变但有明显的乳腺癌或卵巢癌家族史。样本将根据 BRCAness 进行分类，即，他们与 BRCA1/2 突变携带者与具有平均癌症风险的健康对照的相似程度。我们将确定 BRCA1/2 miRNA 谱是否仅限于这些特定基因的改变或反映 DNA 修复的更普遍缺陷可能会增加患卵巢癌的风险。我们将独立地测试 BRCAness miRNA 谱是否足以作为卵巢癌风险分类工具，即使不存在已知的遗传信息。使用病例对照格式，我们将比较基线 miRNA 谱研究对象是参加卵巢癌筛查试验的平均风险女性。我们将计算与对照相比，病例在研究开始时是否更有可能具有 BRCAness miRNA 谱。这这些研究的最终结果将是测试血清 miRNA 是否可以作为生物标志物来识别更多有卵巢癌风险的女性可以从降低风险策略中受益。然后这个组可以是优先用于未来的生物学研究和临床试验。