Project 1 (Couch)

生殖细胞中携带 BRCA1 和 BRCA2 基因失活突变的女性患乳腺癌和卵巢癌的风险显着升高。许多突变携带者能够利用手术预防方案来显着降低患这些癌症的风险。然而，许多其他突变被发现携带意义不确定的变体 (VUS)，其中主要是错义突变。这些 VUS 很少被归类为癌症易感变异或中性变异。因此，许多 VUS 突变携带者不知道他们患癌症的风险是否较高。因此，许多携带中性 VUS 的女性不必要地接受了预防性手术，这会带来严重的长期副作用。在这里，我们建议通过建立基于遗传和实验室测定的 VUS 分析方法来确定整个 BRCAI 和 BRCA2 基因中发现的 VUS 与癌症的相关性。具体来说，在目标 1 中，我们将使用一系列研究对 VUS 进行分类，这些研究重点关注 VUS 患者的癌症家族史和 VUS 患者的乳腺肿瘤病理学。为了促进这种方法的实施，我们最近建立了基于证据的种系突变等位基因解释网络 (ENIGMA)，该联盟旨在通过汇集来自许多研究中心的可用家族信息对额外的 VUS 进行分类。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其他突变进行分类。在目标 2 中，我们将重点关注建立 BRCA2 功能检测对 BRCA2 VUS 分类的敏感性和特异性。我们不会研究 BRCAI，因为该基因中的许多变异已经通过功能研究进行了表征。通过建立与目标 1 的遗传数据相关的测定的敏感性和特异性，可以对许多其他 VUS 进行分类，但家族数据不足以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。这将涉及评估重新分类结果的当前利用情况、提供重新分类工作的结果、提供改进这一过程的教育材料以及评估结果利用的改进。

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.