Germline BAP1 Mutations and Malignant Mesothelioma: Mechanisms and Early Detection

种系 BAP1 突变和恶性间皮瘤：机制和早期检测

• 批准号: 9294995
• 负责人: MICHELE CARBONE
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294995
• 关键词: Address; Affect; Age; Apoptosis; Asbestos; Basal cell carcinoma; Biological Markers; Blood; Cell Culture Techniques; Cell Line; Cell Survival; Cells; Cessation of life; Cholangiocarcinoma; Cultured Cells; Cutaneous Melanoma; Cytoplasm; DNA Damage; Data; Detection; Development; Disease; Disease Progression; Dose; Early Diagnosis; Embryo; Endoplasmic Reticulum; Event; Exposure to; Family; Family member; General Population; Genetic; Growth; HMGB1 gene; Heterozygote; Homeostasis; Human; Impairment; Incidence; Individual; Inflammatory; Injectable; Investigation; Lead; Longitudinal Studies; LoxP-flanked allele; Malignant - descriptor; Malignant Neoplasms; Malignant mesothelioma; Mediating; Mesothelial Cell; Mesothelioma; Mineral Fibers; Modeling; Monitor; Mus; Mutate; Mutation; Pathogenesis; Patients; Penetrance; Peritoneal; Peritoneum; Pleura; Population; Predisposition; Process; Publishing; Reagent; Resistance; Role; Science; Serum; Syndrome; TNF gene; Uveal Melanoma; Virus; Wild Type Mouse; base; cancer type; carcinogenicity; cell growth; cell transformation; cohort; early detection biomarkers; erionite; high risk; improved; in vivo; intraperitoneal; kidney cell; mouse model; mutant; mutation carrier; mutational status; neoplastic cell; novel; outcome forecast; pericardial sac; peripheral blood; public health relevance; sarcoma; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Malignant mesothelioma (MM) is frequent in individuals continuously exposed to carcinogenic mineral fibers such as asbestos and erionite, but it is very rare in those with limited or no exposure. Genetics influences susceptibility to MM, and we have recently demonstrated that carriers of germline BAP1 mutations have increased incidence of multiple cancer types, including MM. In some BAP1-mutation carrying families, MM accounts for more than 50% of deaths, and our central hypothesis is that this may be due to increased susceptibility to MM from exposure to modest amounts of asbestos that would normally not cause MM in the general population. The mechanism(s) by which mutated BAP1 causes MM pathogenesis is unknown. Our preliminary data show a previously uncharacterized BAP1 function in the cytoplasm, wherein BAP1 appears to regulate Ca2+ release from the endoplasmic reticulum and, in turn, apoptosis. Our preliminary data also show that monoallelic BAP1 loss increased susceptibility to low doses of asbestos, and that germline BAP1 mutation carriers have higher levels of serum HMGB1, a critical factor for MM development and progression. In addition, our preliminary investigations show that germline BAP1 mutation carriers with MM have significantly prolonged median survival (5 years) compared to sporadic MM (1 year). Therefore, we hypothesize that, on one hand, BAP1 mutation favors malignant transformation by inhibiting apoptosis and therefore increasing the percentage of cells that accumulate genetic damage, and that, on the other hand, BAP1 mutation may impair the aggressiveness of MM cells by either directly altering tumor cell growth or by affecting the tumor microenvironment. We further hypothesize that monitoring blood levels of HMGB1 in family members who carry BAP1 mutations may facilitate early detection of MM. To address the hypotheses, we will examine the following specific aims: (Aim 1) To elucidate the novel cytoplasmic functions of BAP1 and determine whether BAP1 mutations increase resistance to apoptosis by modulating Ca2+ homeostasis. (Aim 2) To determine whether BAP1 mutations increase susceptibility to MM upon exposure to low amounts of asbestos and elucidate why MM may be less aggressive in BAP1 mutation carriers. (Aim 3) To determine whether HMGB1 is increased in individuals with germline BAP1 mutations. To elucidate the role of cytoplasmic BAP1 and its possible contribution to malignancy, we have assembled a unique cohort of families carrying germline BAP1 mutations and have access to unique models. We will elucidate the mechanisms and genetic alterations that lead to MM in BAP1 mutation carriers using a heterozygous BAP1 mouse model and derived cell cultures. Finally, we will evaluate whether HMGB1 can be used as a biomarker so as to improve our ability to monitor these high-risk individuals for early detection of MM, which will directly impact patients because detection of MM at the early stages of MM progression is strongly correlated to increased survival. These studies will also be relevant to the multiple malignancies associated with the BAP1 cancer syndrome.

 描述（由申请人提供）：恶性间皮瘤（MM）在持续接触石棉和毛沸石等致癌矿物纤维的个体中很常见，但在接触有限或没有接触的个体中非常罕见。遗传学影响对 MM 的易感性， 我们最近证明，种系 BAP1 突变携带者会增加多种癌症类型的发病率，包括多发性骨髓瘤 (MM)。在一些携带 BAP1 突变的家庭中，MM 占死亡人数的 50% 以上，我们的中心假设是，这可能是由于接触适量石棉而增加了对 MM 的易感性，而石棉通常不会在普通人群中引起 MM。突变 BAP1 导致 MM 发病机制尚不清楚。我们的初步数据显示了细胞质中先前未表征的 BAP1 功能，其中 BAP1 似乎调节内质网的 Ca2+ 释放，进而调节细胞凋亡。我们的初步数据还表明，单等位基因 BAP1 缺失增加了对低剂量石棉的敏感性，并且种系 BAP1 突变携带者的血清 HMGB1 水平较高，这是 MM 发生和进展的关键因素。此外，我们的初步研究表明，与散发性 MM（1 年）相比，患有 MM 的种系 BAP1 突变携带者的中位生存期（5 年）显着延长。因此，我们假设，一方面，BAP1突变通过抑制细胞凋亡而促进恶性转化，从而增加累积遗传损伤的细胞百分比，另一方面，BAP1突变可能通过直接改变肿瘤细胞生长或影响肿瘤微环境来损害MM细胞的侵袭性。我们进一步假设，监测携带 BAP1 突变的家庭成员的 HMGB1 血液水平可能有助于早期发现 MM。为了解决这些假设，我们将研究以下具体目标：（目标 1）阐明 BAP1 的新细胞质功能，并确定 BAP1 突变是否通过调节 Ca2+ 稳态来增加细胞凋亡抵抗力。 （目标 2）确定 BAP1 突变是否会在接触少量石棉后增加对 MM 的易感性，并阐明为什么 BAP1 突变携带者的 MM 侵袭性较低。 （目标 3）确定具有种系 BAP1 突变的个体中 HMGB1 是否增加。为了阐明细胞质 BAP1 的作用及其对恶性肿瘤的可能贡献，我们组建了一组携带种系 BAP1 突变的独特家族，并获得了独特的模型。我们将使用杂合 BAP1 小鼠模型和衍生细胞培养物来阐明导致 BAP1 突变携带者 MM 的机制和遗传改变。最后，我们将评估 HMGB1 是否可以用作生物标志物，以提高我们监测这些高危个体以早期发现 MM 的能力，这将直接影响患者，因为在 MM 进展的早期阶段检测到 MM 与提高生存率密切相关。这些研究还将与 BAP1 癌症综合征相关的多种恶性肿瘤相关。