Project 1 (Couch)

在她们的生殖系中携带BRCA1和BRCA2基因失活突变的女性患乳腺癌和卵巢癌的风险显著增加。许多突变携带者能够利用手术预防方案，极大地降低患这些癌症的风险。然而，许多其他人被发现携带不确定意义的变异(VU)，这些变异主要是错义突变。这些VU中很少被归类为癌症易感或中性变异。因此，这些VUS突变的许多携带者不知道他们是否有患癌症的高风险。因此，许多携带VU的女性可能是中性的，不必要地接受预防性手术，这与显著的长期副作用有关。在这里，我们建议通过建立基于遗传和实验室分析的VUS分析方法来确定在整个BRCA1和BRCA2基因中发现的VUS与癌症的相关性。具体地说，在目标1中，我们将使用一系列研究对VU进行分类，重点是VUS患者的癌症家族史和VUS患者的乳腺肿瘤病理。为了促进这一方法，我们最近建立了基于证据的网络来解释种系突变等位基因(EIGMA)，这是一个旨在通过汇集来自许多研究中心的可用家庭信息来对额外的VU进行分类的联盟。只有通过在《谜》中提出的数据共享，才有可能使用基因方法对大量额外的突变进行分类。在目标2中，我们将重点建立BRCA2功能分析在BRCA2 VU分类中的敏感性和特异性。我们不会研究BRCA1，因为该基因中的许多变异已经被功能研究所表征。通过确定检测方法相对于目标1的遗传数据的敏感性和特异性，有可能对许多家系数据不足的其他VU进行分类，以便通过遗传方法进行直接分类。在目标3中，我们将重点开发向提供者和患者提供这些结果的方法。这将涉及评价目前对改叙成果的利用情况，提供改叙工作的成果，提供改进这一进程的教材，以及评价成果利用的改进情况。

Women who carry inactivating mutations in the BRCAI and BRCA2 genes in their germline are at of significantly elevated risk of breast and ovarian cancer. Many mutation carriers are able to take advantage of surgical prevention options that dramatically reduce the risk of developing these cancers. However, many others are found to carry Variants of Uncertain Significance (VUS), which are predominantly missense mutations. Few of these VUS have been classified as cancer predisposing or neutral variants. Thus, many carriers of these VUS mutations do not know if they are at elevated risk of cancer. As a result many women carrying VUS that may be neutral unnecessarily undergo prophylactic surgery that is associated with significant long term side effects. Here we propose to determine the cancer relevance of VUS found throughout the BRCAI and BRCA2 genes by establishing genetic and laboratory assay based methods of VUS analysis. Specifically, in Aim 1 we will classify VUS using a series of studies focusing on family history of cancer of individuals with VUS and on breast tumor pathology of individuals with VUS. To facilitate this approach we have recently established the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), a consortium aimed at classifying additional VUS through pooling of available family information from many research centers. Only through the data sharing proposed in ENIGMA will it be possible to classify a substantial number of additional mutations using genetic approaches. In Aim 2 we will focus on establishing the sensitivity and specificity of BRCA2 functional assays for classification of BRCA2 VUS. We will not study BRCAI because many of the variants in that gene have already been characterized by functional studies. By establishing the sensitivity and specificity of the assays relative to the genetic data from Aim 1 it may be possible to classify many additional VUS with insufficient family data for direct classification by genetic methods. In Aim 3, we will focus on developing methods for providing these results to providers and patients. This will involve evaluation of the current utilization of reclassification results, provision of results of reclassification efforts, provision of educational materials to improve this process, and evaluation of improvements in utilization of results.