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

摘要 肿瘤抑制基因BAP1的胚系突变与遗传性肿瘤相关 易感综合征，BAP1-TPDS(OMIM 614327)，我们和其他人在2011年发现的。症候群是 与四种癌症的易感性有关：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素细胞皮肤损害(BAP1-失活黑素细胞 肿瘤)。其他癌症也被报道发生在生殖系BAP1突变的患者身上，但目前尚不清楚 它们是否为BAP1-TPDS的一部分。自它被刻画以来，已经有200多个不同的家庭 随着越来越多的致病/可能致病变异被存放在ClinVar中，报告了这一现象。我们的我们的 Exome Aggregation Consortium(ExAC)数据库中的变异体分析表明，BAP1-TPDS是 在癌症患者中报告不足。 BAP1是一种去泛素化水解酶，具有四个已知功能：(I)细胞周期调节和细胞 生长，(2)DNA损伤修复，(3)染色质重塑和基因表达的调节，以及(4)调节 对细胞凋亡的影响。这些复杂的功能角色中，哪一种负责其肿瘤抑制功能 未知，需要确定能够使识别出的最佳实验模型体系(S)来预测 变异体的临床意义不确定。我们的目标是描述临床上 与BAP1不同胚系变体相关的表型，以剖析其复杂的功能。我们会 解决以下关键障碍：1)BAP1中报告的生殖系变异数量有限，已知 临床表型；2)需要实验模型系统(S)评估不同编码对临床的影响 BAP1中的变异；以及3)评估非编码变异在种系失活中的作用的必要性 BAP1. 目的：扩大对BAP1-TPDS临床表型的认识，并与变异体相关 在基因中。 特异性AIM2：建立评估BAP1胚系错义变异的实验模型系统 不确定的意义。 目的：评估非编码变异在BAP1基因种系失活中的作用。 科学和翻译影响：这些研究的结果有可能为临床医生提供 需要关键的资源，以解决适当咨询和管理患者和 BAP1基因发生胚系突变的家系。这一结果也将为基础科学家提供重要的资源 以进一步研究BAP1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.