Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations
Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations
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DOI：
10.1002/path.5110
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发表时间：
2018-09-01
影响因子：
7.3
通讯作者：
Schultheis, Anne Maria
中科院分区：
文献类型：
--
作者：
Alidousty, Christina;Baar, Till;Schultheis, Anne Maria
间变性淋巴瘤激酶（ALK）重排定义了非小细胞肺癌（NSCLC）的一个独特的分子亚型。尽管ALK抑制剂在ALK+肺癌患者中具有良好的初始疗效，但耐药性几乎不可避免地发生。到目前为止，还没有可靠的生物标志物可以识别复发风险较高的患者。在这里，我们通过NanoString nCounter技术分析了53个有和没有TP53突变的ALK+肿瘤和ALK+ NSCLC细胞系。我们发现ALK+ NSCLC中早期TP53突变的共同出现可导致染色体不稳定：24%的TP53突变患者显示已知癌症基因的扩增，如MYC（14%）、CCND1（10%）、TERT（5%）、BIRC2（5%）、ORAOV1（5%）和YAP1（5%）。与野生型细胞相比，myc过表达的ALK+ tp53突变细胞具有增殖优势。ChIP-Seq数据显示，MYC结合位点位于EML4的启动子区域，并且MYC在ALK+ tp53突变细胞中的过表达导致EML4-ALK上调，这表明MYC拷贝数增加的患者可能存在MYC依赖性耐药机制。我们的研究表明，ALK+ NSCLC代表了一个比最初认为的更异质性的肿瘤亚群，并且该特定癌症类型中的TP53突变定义了一个具有染色体不稳定性的肿瘤亚群，导致致病性畸变的共同发生。(c) 2018年作者。由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版的病理学杂志。
The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumors with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC-overexpressing ALK+ TP53-mutated cells had a proliferative advantage compared to wild-type cells. ChIP-Seq data revealed MYC-binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53-mutated cells resulted in an upregulation of EML4-ALK, indicating a potential MYC-dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumors than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumors that harbour chromosomal instability, leading to the co-occurrence of pathogenic aberrations. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.