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首页> 外文期刊>Oncogene >Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma
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Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma

机译：TERT基因在恶性胸膜间皮瘤中的过表达和启动子突变

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Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT鈥揚CR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 鈥榟ot spot鈥?of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P <0.01), and they were frequently associated with CDKN2A gene inactivation (P =0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.
机译：恶性胸膜间皮瘤（MPM）是一种非常恶性的肿瘤，尚无已知的治疗方法。为了发展新的治疗策略，需要对间皮癌变的分子机制有更好的了解。像所有癌细胞一样，MPM需要保持端粒长度以防止衰老。先前的研究表明，MPM中的端粒延长机制主要基于端粒酶活性。因此，我们通过分析其在MPM中的基因表达并研究其上调的潜在机制，来研究关键的催化酶TERT（端粒酶逆转录酶）。我们使用了大量的MPM集合，其中包括培养物中的61 MPM和71个冷冻的MPM肿瘤样品。通过定量RT'-CR评估TERT mRNA的表达，与正常的间皮细胞相比，培养物中MPM的表达过高，与正常的胸膜相比，MPM肿瘤样品中的过表达。我们在培养的MPM和MPM肿瘤样品中的总频率为15％的iTERT基因核心启动子中鉴定了一个突变的“热点”。此外，数据清楚地将 TERT启动子中的突变鉴定为MPM中 TERT mRNA上调的机制。相反，基因拷贝数扩增与TERT过表达无关。然后，我们分析了在 TERT启动子中有突变的MPM的临床病理，病因学和遗传学特征。在患有肉瘤样组织学亚型的MPM中，TERT启动子突变更为频繁（

0.01），并且经常与CDKN2A基因失活有关（

0.03）。总之，MPM的一个子集呈现出 TERT启动子突变，从而导致 TERT mRNA上调。这是MPM中发现的第一个复发性功能获得性致癌突变。

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