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

分子发病机制的研究重点是定义导致癌症和出生缺陷等常见疾病遗传易感性的基因变化。目前正在研究的是遗传性乳腺癌和卵巢癌基因BRCA1和BRCA2。这些蛋白质的生物学功能目前尚不清楚。之前，我们发现了哪些蛋白质与BRCA1特异性相互作用。我们还发现BRCA1对控制其他基因的表达很重要，并在DNA修复中发挥作用。最近的实验表明，BRCA1似乎有助于识别和消除可能形成肿瘤的细胞。我们现在知道，与这些基因中的遗传变异相关的乳腺癌、卵巢癌和前列腺癌风险的增加是由于这些突变的蛋白质在DNA修复途径中无法发挥作用。我们使用酵母细胞作为实验模型来测试在人类中发现的突变的功能后果。我们还开发了一个系统，用于识别与BRCA1相互作用的蛋白质。 在过去，我们应用生物信息学方法来探测基因组结构在蛋白质进化中可能发挥的作用。 对BRCA1和BRCA2基因的研究使我们发现了一种特定类型的基因结构与进化变化率之间的新联系。 这一观察结果似乎可以推广到几乎任何基因，并适用于所有后生动物谱系。我们最近完成了对六个基因组中每个基因组的所有外显子的研究。我们在较小样本中观察到的规则在这个较大的集合中得到了证实。 本节创建并维护了乳腺癌基因BRCA1和BRCA2突变的数据库，该科学资源由研究人员使用。 在过去的一年中，我们向数据库中添加了信息，使用户能够评估突变的临床和功能意义。

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. The biological function of these proteins is currently unknown. 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. Recent experiments has 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 used yeast cells as an experimental model to test the functional consequences of mutations found in humans. We have also developed a system for identifying proteins that interact with BRCA1. 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.