Spectrum of clinical phenotype of the BAP1-tumor predisposition syndrome (BAP1-TPDS)

摘要 肿瘤抑制基因BAP 1的生殖系突变与遗传性肿瘤相关 易感综合征，BAP 1-TPDS（OMIM 614327），我们和其他人在2011年确定。该综合征是 与主要四种癌症的易感性相关：葡萄膜黑色素瘤，间皮瘤，皮肤黑色素瘤， 和肾细胞癌，以及癌前黑色素细胞皮肤病变（BAP 1-失活黑色素细胞 肿瘤）。在具有生殖系BAP 1突变的患者中也报告了其他癌症，但尚不清楚 是否属于BAP 1-TPDS。自从它的特性，200多个不同的家庭已被 报告了越来越多的致病性/可能致病性变体被存放在ClinVar中。我们的我们的 外显子组聚集联盟（ExAC）数据库中的变体分析表明，BAP 1-TPDS是 在癌症患者中被低估。 BAP 1是一种去泛素化水解酶，具有四种已知功能：（i）细胞周期调控和细胞凋亡。 生长，（ii）DNA损伤修复，（iii）染色质重塑和基因表达调控，以及（iv）调控 细胞凋亡。在这些复杂的功能性作用中，哪一个是其肿瘤抑制功能的原因， 未知，并且需要被确定以使得能够识别要预测的最佳实验模型系统 不确定意义的变异的临床意义。我们的目标是描述 与BAP 1的不同种系变体相关的表型，以剖析其复杂的功能。我们将 解决了以下关键障碍：1）BAP 1中报告的有限数量的种系变异， 临床表型; 2）需要实验模型系统来评估不同编码的临床影响 BAP 1中的变异;以及3）需要评估非编码变异在BAP 1的种系失活中的作用。 BAP 1. 具体目标1：扩大对BAP 1-TPDS临床表型的理解，并与变异体相关 在基因中。 具体目标2：建立实验模型系统，用于评估BAP 1种系错义变体， 不确定的意义。 特定目标3：评估非编码变体在BAP 1种系失活中的作用。 科学和转化影响：这些研究的结果有可能为临床医生提供 解决对患者进行适当咨询和管理的主要障碍所需的关键资源， BAP 1基因突变的家族。研究结果还将为基础科学家提供重要的资源 用于进一步研究BAP 1的各种肿瘤抑制功能，以及NCI的关键资源 ClinGen和ClinVar项目。

ABSTRACT Germline mutation in the tumor suppressor gene BAP1 is associated with the hereditary tumor predisposition syndrome, BAP1-TPDS (OMIM 614327), that we and others identified in 2011. The syndrome is associated with predisposition to mainly four cancers: uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma in addition to a preneoplastic melanocytic skin lesions (BAP1-Inactivated Melanocytic Tumors). Other cancers have been also reported in patients with germline BAP1 mutation but it is not clear whether they are part of the BAP1-TPDS. Since its characterization, more than 200 distinct families have been reported with an increasing number of pathogenic/likely pathogenic variants being deposited in ClinVar. Our our analysis of variants in the Exome Aggregation Consortium (ExAC) database suggests that BAP1-TPDS is underreported in cancer patients. BAP1 is a deubiquitinating hydrolase that has four known functions: (i) cell cycle regulation and cell growth, (ii) DNA damage repair, (iii) chromatin remodelling and regulation of gene expression, and (iv) regulation of apoptosis. Which of these complex functional roles are responsible for its tumor suppressor function is unknown, and needs to be determined to enable identification of the best experimental model system(s) to predict the clinical significance of the variants of uncertain significance. Our goal is to characterize the clinical phenotypes associated with different germline variants of BAP1 in order to dissect its complex functions. We will address the following critical barriers: 1) the limited number of reported germline variants in BAP1 with known clinical phenotype; 2) the need for experimental model system(s) to assess the clinical impact of different coding variants in BAP1; and 3) the need to assess the contribution of non-coding variants in germline inactivation of BAP1. Specific Aim1: To expand the understanding of the clinical phenotypes of BAP1-TPDS and correlate with variants in the gene. Specific Aim2: Establish experimental model systems for evaluation of BAP1 germline missense variants of uncertain significance. Specific Aim3: To assess the contribution of non-coding variants in germline inactivation of BAP1. Scientific and Translational Impact: The outcomes of these studies have the potential to provide clinicians with crucial resources needed to address a major barrier for proper counseling and management of patients and families with germline mutations in BAP1. The results will also provide basic scientists with important resources for further studies of various tumor suppressor functions of BAP1, as well as crucial resources for the NCI ClinGen and ClinVar projects.