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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：恶性间皮瘤（MM）经常在不断暴露于致癌矿物纤维（例如石棉和erionite）的个体中，但在有限或没有暴露的人中非常罕见。遗传学影响对MM的敏感性，我们最近证明，种系BAP1突变的载体具有多种癌症类型的发病率，包括MM。在某些BAP1携带家庭中，MM占死亡人数的50％以上，我们的中心假设是，这可能是由于对MM的易感性增加了，从暴露到适度的石棉，通常不会在普通人群中引起MM。突变的BAP1引起MM发病机理的机制尚不清楚。我们的初步数据表明，在细胞质中，先前未表征的BAP1功能，其中BAP1似乎调节了从内质网中释放的Ca2+释放，又又凋亡。我们的初步数据还表明，Monoallelic BAP1损失增加了对低剂量石棉的敏感性，并且该种系BAP1突变载体具有更高水平的血清HMGB1，这是MM发育和进展的关键因素。此外，我们的初步研究表明，与零星MM相比，具有MM的种系BAP1突变载体显着延长了中位生存期（5年）（1年）。因此，我们假设BAP1突变通过抑制凋亡，从而增加了恶性转化，从而增加了积累遗传损害的细胞的百分比，并且另一方面，另一方面，BAP1突变可能会通过直接改变肿瘤细胞生长或通过影响肿瘤Microenvorment损害MM细胞的攻击性。我们进一步假设，在携带BAP1突变的家庭成员中监测HMGB1的血液水平可能有助于早期发现MM。为了解决假设，我们将研究以下特定目的：（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+稳态来增加对凋亡的抗性。（AIM 2）确定BAP1突变是否会在暴露于低棉石棉的情况下增加对MM的敏感性，并阐明为什么MM在BAP1突变载体中可能不那么侵略性。（目标3）确定种系BAP1突变个体中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，我们组装了一个独特的携带生殖线BAP1突变的家庭队列，并可以访问独特的模型。我们将阐明使用杂合BAP1小鼠模型和衍生的细胞培养物在BAP1突变载体中导致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风险个体以早期检测MM的能力，这将直接影响患者，因为在MM进展的早期发现MM与生存率增加密切相关。这些研究也将与与BAP1癌症综合征相关的多重恶性肿瘤有关。