Project 1 (Couch)

在生殖细胞中携带BRCAI和BRCA2基因失活突变的女性患乳腺癌和卵巢癌的风险显著升高。许多突变携带者能够利用手术预防方案，大大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体（VUS），主要是错义突变。这些VUS中很少被归类为癌症易感或中性变体。因此，这些VUS突变的许多携带者不知道他们是否处于癌症的高风险中。因此，许多携带可能是中性的VUS的妇女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检测的VUS分析方法来确定在BRCAI和BRCA2基因中发现的VUS与癌症的相关性。具体而言，在目标1中，我们将使用一系列研究对VUS进行分类，这些研究侧重于VUS个体的癌症家族史和VUS个体的乳腺肿瘤病理学。为了促进这种方法，我们最近建立了基于证据的网络的生殖系突变等位基因的解释（ENIGMA），一个联盟，旨在通过汇集来自许多研究中心的可用的家庭信息来分类额外的VUS。只有通过ENIGMA中提出的数据共享，才有可能使用遗传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BRCA 2功能检测对BRCA 2 VUS分类的灵敏度和特异性。我们不会研究BRCAI，因为该基因的许多变体已经通过功能研究进行了表征。通过确定检测相对于目标1遗传数据的灵敏度和特异性，可能对许多其他家族数据不足以通过遗传方法直接分类的VUS进行分类。在目标3中，我们将专注于开发向提供者和患者提供这些结果的方法。这将涉及评价目前利用改叙结果的情况，提供改叙工作的结果，提供教育材料以改进这一进程，以及评价在利用结果方面的改进情况。

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.