Germline BAP1 Mutations and Malignant Mesothelioma: Mechanisms and Early Detection

 描述（由申请人提供）：恶性间皮瘤（MM）常见于持续暴露于致癌矿物纤维（如石棉和毛沸石）的个体，但在有限暴露或无暴露的个体中非常罕见。遗传因素影响MM的易感性， 我们最近证明，生殖系BAP1突变携带者增加了多种癌症类型的发病率，包括MM。在一些BAP1突变携带家庭中，MM占死亡人数的50%以上，我们的中心假设是，这可能是由于暴露于适量的石棉而增加了对MM的易感性，而石棉在一般人群中通常不会引起MM。突变的BAP 1引起MM发病机制的机制尚不清楚。我们的初步数据显示，以前未表征的BAP1在细胞质中的功能，其中BAP1似乎调节Ca2+从内质网释放，反过来，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易感性，并且生殖系BAP1突变携带者具有较高的血清HMGB1水平，这是MM发展和进展的关键因素。此外，我们的初步研究表明，与散发性MM（1年）相比，MM生殖系BAP 1突变携带者的中位生存期（5年）显著延长。因此，我们假设，一方面，BAP 1突变通过抑制细胞凋亡从而增加积累遗传损伤的细胞的百分比而有利于恶性转化，另一方面，BAP 1突变可能通过直接改变肿瘤细胞生长或通过影响肿瘤微环境而损害MM细胞的侵袭性。我们进一步假设，监测携带BAP 1突变的家庭成员的血液中HMGB1水平可能有助于MM的早期检测。为了解决这一假设，我们将研究以下具体目标：（目的1）阐明BAP 1的新的细胞质功能，并确定BAP 1突变是否通过调节Ca 2+稳态增加对细胞凋亡的抵抗。(Aim 2）确定BAP 1突变是否增加暴露于低量石棉后对MM的易感性，并阐明为什么MM在BAP 1突变携带者中的侵袭性较低。(Aim 3）确定HMGB1在具有生殖系BAP 1突变的个体中是否增加。为了阐明细胞质BAP1的作用及其对恶性肿瘤的可能贡献，我们已经组装了一个独特的携带种系BAP1突变的家族队列，并获得了独特的模型。我们将使用杂合子BAP 1小鼠模型和衍生细胞培养物阐明导致BAP 1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进展的早期阶段检测MM与生存率增加密切相关。这些研究也将与BAP 1癌症综合征相关的多种恶性肿瘤相关。

 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.