Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.
Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.
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DOI：
10.1158/0008-5472.can-14-1328
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发表时间：
2014-08-15
期刊：
影响因子：
11.2
通讯作者：
Testa JR
中科院分区：
文献类型：
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作者：
Xu J;Kadariya Y;Cheung M;Pei J;Talarchek J;Sementino E;Tan Y;Menges CW;Cai KQ;Litwin S;Peng H;Karar J;Rauscher FJ;Testa JR
恶性间皮瘤是高度侵袭性的肿瘤，通常由接触石棉引起。种系BAP1失活突变易患间皮瘤和某些其他癌症。然而，为什么在一些BAP1家族中间皮瘤是主要的恶性肿瘤，而在其他BAP1家族中则不是，以及在BAP1突变携带者中间皮瘤的发展是否需要暴露于石棉，这些都尚不清楚。为了通过实验解决这些问题，我们建立了Bap1+/−敲除小鼠模型，以评估其在长期暴露于石棉后对间皮瘤的易感性。Bap1+/−小鼠的石棉诱导间皮瘤发病率明显高于WT组（分别为73%对32%）。此外，与WT动物相比，Bap1+/−小鼠的间皮瘤发生速度加快（初始暴露后中位生存期分别为43周和55周），侵袭性和增殖性增加。未暴露的Bap1+/−小鼠未见自发性间皮瘤，随访至87周龄。来自Bap1+/−小鼠的间皮瘤细胞显示Bap1双等位基因失活，这与Bap1作为隐性癌症易感基因的作用一致。与野生型小鼠不同，Bap1+/−小鼠的间皮瘤不需要Cdkn2a的纯合缺失。然而，来自Bap1+/−小鼠的正常间皮瘤细胞和间皮瘤细胞通过p16（Ink4a）不依赖的机制显示Rb下调，这表明Bap1+/−小鼠对间皮瘤的易感性可能部分是由Bap1和Rb之间的合作促进的。与人类疾病相似，这些无偏倚的遗传发现表明BAP1突变携带者易受石棉致瘤作用的影响，并表明间皮瘤的高外显率需要这样的环境暴露。
Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers, are not known. To address these questions experimentally, we generated a Bap1+/− knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1+/− mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than WT littermates(73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/− mice compared to WT animals(median survival, 43 weeks versus 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1+/− mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1+/− mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in wild-type mice, mesotheliomas from Bap1+/− mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1+/− mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/− mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.