INSERM, U674, Paris, France.
Am J Pathol. 2011 Feb;178(2):881-94. doi: 10.1016/j.ajpath.2010.10.039.
Malignant mesothelioma (MM) is an aggressive tumor with a poor prognosis mainly linked to past asbestos exposure. Murine models of MM based on fiber exposure have been developed to elucidate the mechanism of mesothelioma formation. Genomic alterations in murine MM have now been partially characterized. To gain insight into the pathophysiology of mesothelioma, 16 murine and 35 human mesotheliomas were characterized by array-comparative genomic hybridization and were screened for common genomic alterations. Alteration of the 9p21 human region, often by biallelic deletion, was the most frequent alteration in both species, in agreement with the CDKN2A/CDKN2B locus deletion in human disease and murine models. Other shared aberrations were losses of 1p36.3-p35 and 13q14-q33 and gains of 5p15.3-p13 regions. However, some differences were noted, such as absence of recurrent alterations in mouse regions corresponding to human chromosome 22. Comparison between altered recurrent regions in asbestos-exposed and non-asbestos-exposed patients showed a significant difference in the 14q11.2-q21 region, which was also lost in fiber-induced murine mesothelioma. A correlation was also demonstrated between genomic instability and tumorigenicity of human mesothelioma xenografts in nude mice. Overall, these data show similarities between murine and human disease, and contribute to the understanding of the influence of fibers in the pathogenesis of mesothelioma and validation of the murine model for preclinical testing.
恶性间皮瘤（MM）是一种侵袭性肿瘤，预后不良，主要与过去的石棉暴露有关。已经开发出基于纤维暴露的 MM 小鼠模型，以阐明间皮瘤形成的机制。现在已经部分描述了 MM 小鼠的基因组改变。为了深入了解间皮瘤的病理生理学，对 16 种鼠源性和 35 种人源性间皮瘤进行了基于阵列比较基因组杂交的特征分析，并对常见的基因组改变进行了筛选。9p21 人类区域的改变，通常是双等位基因缺失，在这两个物种中是最常见的改变，这与人类疾病和小鼠模型中 CDKN2A/CDKN2B 基因座缺失一致。其他共同的异常改变包括 1p36.3-p35 和 13q14-q33 的缺失和 5p15.3-p13 区域的获得。然而，也注意到了一些差异，例如在对应于人类染色体 22 的小鼠区域中没有反复出现的改变。暴露于石棉和非石棉的患者中改变的重复区域的比较显示，14q11.2-q21 区域存在显著差异，该区域在纤维诱导的 MM 中也丢失了。还证明了基因组不稳定性与裸鼠中人源性间皮瘤异种移植物的致瘤性之间存在相关性。总体而言，这些数据显示了 MM 小鼠模型和人类疾病之间的相似性，并有助于理解纤维在间皮瘤发病机制中的影响以及验证 MM 小鼠模型用于临床前测试。
