IHC Test for BRCA1 Hereditary Ovarian Cancer

BRCA1 遗传性卵巢癌的 IHC 检测

• 批准号: 8239640
• 负责人: Jeffrey T Holt
• 金额: $ 39.92万
• 依托单位: TISSUE GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239640
• 关键词: Address; Affect; Animals; Antibodies; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Biological Assay; Blood Glucose; Blood specimen; Breast; C-terminal; Cancer Patient; Cancer-Predisposing Gene; Cholesterol; Cisplatin; Clinical Research; Clinical Trials; Communities; Companions; DNA Sequence; Data; Defect; Development; Diagnosis; Diagnostic; Employee Strikes; FDA approved; Family; Family member; Funding; Gene Mutation; Genes; Genetic; Genetic Counseling; Genetic Polymorphism; Genetic Screening; Genetic screening method; Health; Hereditary Breast Carcinoma; Hereditary Disease; Hereditary Malignant Neoplasm; Hospitals; Immunohistochemistry; Individual; Inherited; Knowledge; Legal patent; Malignant Neoplasms; Malignant neoplasm of ovary; Marketing; Medical; Methods; Mutation; N-terminal; Ovarian; Ovarian Tissue; Patients; Phase; Pilot Projects; Population; Preventive; Process; Protein Truncation; Proteins; Protocols documentation; Publishing; Relative (related person); Reporting; Research; Resolution; Risk; Sample Size; Sampling; Screening procedure; Sensitivity and Specificity; Serum; Small Business Innovation Research Grant; Specificity; System; Tamoxifen; Testing; Time; Tissue Sample; Tissues; Variant; anticancer research; base; cancer genetics; cancer risk; cost; high risk; inhibitor/antagonist; malignant breast neoplasm; mutant; mutation carrier; novel; prevent; research and development; technological innovation; tissue preparation

DESCRIPTION (provided by applicant): This is a Fast-Track proposal to develop a tissue-based genetic test for BRCA1 hereditary ovarian cancer. Ten percent of unselected US ovarian cancers are BRCA1 hereditary cancers with truncating mutations in the BRCA1 gene. It is important to know which ovarian cancer patients have BRCA1 hereditary ovarian cancer because BRCA1 patients have an increased risk of breast cancer and their relatives with mutations have an increased risk of breast and ovarian cancer. These subsequent cancers would be discovered early or prevented if widespread genetic screening was available and recent data indicates that BRCA hereditary cancers respond to targeted therapies such as cis-platinum and PARP inhibitors. We have developed an antibody-based tissue truncation method to identify BRCA1 hereditary cancers and were able to correctly identify 5/5 BRCA1 hereditary cancers and 20/200 sporadic cancers in a pilot study. This approach visualizes protein truncation by showing with immunohistochemistry (IHC) that the N-terminus is present but the C-terminus is absent. The product (test) will be an antibody-based IHC diagnostic kit for cancer tissue samples which hospital labs will use to identify hereditary cancers. We have already successful developed and published a similar IHC method to identify BRCA2 hereditary cancers with sensitivity of 95% and specificity of 98%.The milestones for the Phase I proposal are: 1) Determine optimal tissue preparation protocols for IHC with both N-terminal and C-terminal BRCA1 antibodies. 2) Develop a quantitative scoring system for N-terminal and C-Terminal BRCA1 immunostaining on ovarian tissues with intra-assay variability of 15% and inter-assay variability of 20% or less. 3) Demonstrate that a C-terminal to N-terminal ratio for protein truncation (BRCA1 Truncation Ratio) can distinguish 20 hereditary BRCA1 ovarian cancers from 50 sporadic ovarian cases with greater than 90% sensitivity and specificity (comparing different scoring systems). Upon completion of these milestones we would pursue the following Phase II milestones: Milestone 1a: Determine the specificity of the BRCA1 truncation ratio in 20 ovarian cancers in patients known to have BRCA2 mutations. Milestone 1b: Determine the specificity of the truncation ratio in 10 ovarian cancers in patients reported to have polymorphisms/missense variants of BRCA1. Milestone 2: Determine if the BRCA1 truncation test can achieve 90% sensitivity and specificity in a clinical trial of 300 ovarian cancer samples (sample size to provide 30 BRCA1 hereditary cancers). The medical application of breast/ovarian cancer genetic testing is a proven market since Myriad Genetics annually grosses $150 million on DNA sequencing. PUBLIC HEALTH RELEVANCE: Successful completion of this Fast-track research will establish a new tissue- based genetic test for BRCA1 hereditary ovarian cancer based on an IHC method to visualize protein truncation. This simpler more widely applicable approach will help predict appropriate therapy for patients with BRCA1 hereditary cancer and identify many more families with hereditary breast and ovarian cancer and consequently help patients and their relatives by identifying individuals likely to develop subsequent breast or ovarian cancer which might be prevented by tamoxifen and/or screening.

描述(由申请人提供)：这是一项快速通道提案，旨在开发一种基于组织的BRCA1遗传性卵巢癌基因测试。10%的未经选择的美国卵巢癌是BRCA1遗传性癌症，BRCA1基因发生截断突变。重要的是要知道哪些卵巢癌患者患有BRCA1遗传性卵巢癌，因为BRCA1患者患乳腺癌的风险增加，其突变的亲属患乳腺癌和卵巢癌的风险也增加。如果可以进行广泛的基因筛查，并且最近的数据表明BRCA遗传性癌症对靶向治疗如顺铂和PARP抑制剂有反应，这些后续癌症将被及早发现或预防。我们开发了一种基于抗体的组织截断方法来识别BRCA1遗传癌，在一项初步研究中，我们能够正确识别5/5的BRCA1遗传癌和20/200的散发性癌症。这种方法通过免疫组织化学(IHC)显示N-末端存在但C-末端缺失来可视化蛋白质截断。该产品(检测)将是一种基于抗体的IHC癌症组织样本诊断试剂盒，医院实验室将使用该试剂盒来识别遗传性癌症。我们已经成功地开发并发表了一种类似的免疫组化方法来识别BRCA2遗传性癌症，敏感性为95%，特异性为98%。I期方案的里程碑是：1)确定N端和C端BRCA1抗体的IHC的最佳组织制备方案。2)建立卵巢组织N-末端和C-末端BRCA1免疫染色定量评分系统，批内变异系数为15%，批间变异系数为20%或更低。3)通过比较不同的评分系统，证明C-末端与N-末端蛋白质截短比率(BRCA1截短率)可以区分20例遗传性BRCA1卵巢癌和50例散发性卵巢癌，其敏感性和特异性均大于90%。在完成这些里程碑后，我们将追求以下第二阶段里程碑：里程碑1a：确定已知具有BRCA2突变的20例卵巢癌患者中BRCA1截短比率的特异性。里程碑1b：确定10例卵巢癌中BRCA1基因多态/错义变异患者截短率的特异性。里程碑2：在300个卵巢癌样本的临床试验中，确定BRCA1截断测试是否可以达到90%的灵敏度和特异度(样本大小可提供30个BRCA1遗传性癌症)。乳腺癌/卵巢癌基因检测的医疗应用是一个经过验证的市场，因为Myriad Genetics每年的DNA测序收入为1.5亿美元。 公共卫生相关性：这项快速研究的成功完成将为BRCA1遗传性卵巢癌建立一种新的基于组织的基因测试，该测试基于IHC方法以可视化蛋白质截断。这种更简单、适用范围更广的方法将有助于预测BRCA1遗传性癌症患者的适当治疗，并识别更多患有遗传性乳腺癌和卵巢癌的家庭，从而通过识别可能患上后续乳腺癌或卵巢癌的个体来帮助患者及其亲属，这些个人可能通过他莫昔芬和/或筛查来预防。