The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer

BRCA1和BRCA2基因在乳腺癌发病机制中的作用

• 批准号: 8149414
• 负责人: Lawrence C Brody
• 金额: $ 12.68万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149414
• 关键词: BRCA1 gene; BRCA2 gene; Bioinformatics; Clinical; DNA Repair; DNA Repair Pathway; Databases; Disease; Evolution; Exons; Failure; Gene Structure; Genes; Genetic; Genetic Predisposition to Disease; Genome; Goals; Lead; Malignant neoplasm of ovary; Medical; Methods; Molecular; Mutate; Mutation; Oncogenes; Ovarian; Pathogenesis; Play; Predisposition; Process; Proteins; Research; Research Personnel; Resources; Role; Variant; malignant breast neoplasm

Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Currently under investigation are the inherited breast and ovarian cancer genes, BRCA1 and BRCA2. These proteins appear to be involved in DNA repair. Previously, we discovered which proteins specifically interact with BRCA1. We also have found that BRCA1 is important for controlling the expression of other genes and is plays a role in DNA repair. Additional experiments under this project have revealed that BRCA1 appears to help in the process of recognizing and eliminating cells that may progress to form tumors. We now know that the increase in breast, ovarian and prostate cancer risk associated with genetic variants in these genes is due to a failure of these mutated proteins to function in the DNA repair pathway. We are now collaborating on a project designed to understand the molecular changes that occur in ovarian tumors. A large percentage of ovarian tumors occur in women who carry mutations in their BRCA1 or BRCA2 genes. We have recently identified changes in genes that may be associated to the formation of in ovarian tumors. These changes can now be related to specific clinical outcomes and responses to treatment. In the past, we applied a bioinformatics approach to probe the role that genomic structure may play in protein evolution. The study of the BRCA1 and BRCA2 genes has led us to discover a new connection between a specific type of gene structure and evolutionary rates of changes. This observation appears to be generalizable to almost any gene and holds true across all metazoan lineages. We recently completed the study of all the exons in each of six genomes. The rules we observed for our smaller sample have been confirmed in this larger set. This section created and maintains a database of mutations in the breast cancer genes, BRCA1 and BRCA2, this scientific resource is used by investigators through out the word. In the past year we have added information to the database that will allow users to assess the clinical and functional significance of mutations. As an extension of the database, we are working on methods to determine which mutations in BRCA1 and BRCA2 are of medical significance.

分子发病机理中的研究集中在定义基因的变化，这些基因是遗传性疾病（例如癌症和先天缺陷）的敏感性的基因的变化。目前正在研究的是遗传性的乳腺癌和卵巢癌基因BRCA1和BRCA2。 这些蛋白似乎参与了DNA修复。以前，我们发现了哪些蛋白质与BRCA1专门相互作用。我们还发现，BRCA1对于控制其他基因的表达很重要，并且在DNA修复中起作用。该项目下的其他实验表明，BRCA1似乎有助于识别和消除可能形成肿瘤的细胞的过程。我们现在知道，这些基因中与遗传变异有关的乳腺，卵巢和前列腺癌风险的增加是由于这些突变蛋白在DNA修复途径中起作用。 我们现在正在合作，旨在了解卵巢肿瘤中发生的分子变化。 在其BRCA1或BRCA2基因中携带突变的女性中发生了很大一部分卵巢肿瘤。我们最近确定了可能与卵巢肿瘤形成有关的基因变化。这些变化现在可以与特定的临床结果和对治疗的反应有关。 过去，我们采用了一种生物信息学方法来探测基因组结构在蛋白质进化中的作用。 对BRCA1和BRCA2基因的研究使我们发现了特定类型的基因结构与变化的进化速率之间的新联系。 这种观察似乎几乎可以推广到任何基因，并且在所有后生谱系中都具有真实性。我们最近完成了六个基因组中每个外显子的研究。我们观察到的较小样本的规则已在此较大的集合中得到了确认。 本节创建并维护了乳腺癌基因BRCA1和BRCA2中突变的数据库，研究人员通过该词使用了该科学资源。 在过去的一年中，我们将信息添加到数据库中，这些信息将允许用户评估突变的临床和功能意义。作为数据库的扩展，我们正在研究确定BRCA1和BRCA2中哪些突变的方法。