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首页> 外文期刊>British Journal of Cancer >Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients
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Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients

机译：在肺癌患者的血液DNA样本中发现了 PPM1D 的截短突变

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Background: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. Methods: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. Results: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes ( BAX and MDM2 ). Conclusions: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy.
机译：背景：PPM1D（WIP1）通过去磷酸化负调控包括p53肿瘤抑制因子在内的许多蛋白质。最近在患有乳腺癌，卵巢癌或结肠直肠癌的患者的血细胞中发现了PPM1D外显子6的截短突变（无意义和移码）。这些突变体编码具有保留的磷酸酶活性的功能增益PPM1D。它们在致癌作用中的意义尚不清楚。方法：对543例非小细胞肺癌（NSCLC）患者血液DNA中的PPM1D外显子6进行测序。将选定的PPM1D改变（Arg458X，Lys469Glu）的功能意义与野生型基因进行比较，并通过重组DNA技术，免疫印迹和荧光素酶报告基因检测进行了检查。结果：5例NSCLC患者中发现了移码突变（5/543; 0.92％），所有患者均患有鳞状细胞癌（5/328; 1.5％）。在进行采血之前，所有具有突变的患者都要接受DNA破坏剂的治疗，这是化疗方案的一部分。功能测试表明，截短的突变Arg458X导致PPM1D对p53丝氨酸15的去磷酸化活性增强，而Lys469Glu版本与野生型等效。 PPM1D的两个版本（野生型，Arg458X，Lys469Glu）均未显着调节p53激活被检p53靶基因（BAX和MDM2）启动子的能力。结论：PPM1D的截短突变在NSCLC患者的血液DNA中存在的频率与为卵巢癌患者确定的百分比相似。我们的发现提出了一个疑问，即检测到的病变是否是化学疗法的结果。

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