Genetic mutations associated with lung cancer metastasis to the brain
Genetic mutations associated with lung cancer metastasis to the brain
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DOI：
10.1093/mutage/gey003
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发表时间：
2018-03-01
期刊：
影响因子：
2.7
通讯作者：
Bahassi, El Mustapha
中科院分区：
文献类型：
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作者：
Aljohani, Hashim M.;Aittaleb, Mohamed;Bahassi, El Mustapha
大约90%的癌症死亡是由原发肿瘤的转移扩散引起的。在所有参与癌症发生的过程中，局部侵袭和转移的形成在临床上是最相关的，但在分子水平上却是最不被了解的。作为转移的屏障，细胞在循环中通常会经历一个被称为“失巢”的凋亡过程。最近在分离和鉴定罕见的循环肿瘤细胞(CTCs)方面的技术进步将使人们能够更好地了解失巢凋亡抵抗。对耐失巢细胞的详细分子和功能分析可能有助于深入了解癌症转移的生物学，并有助于确定预防癌症扩散的新靶点。为了揭示控制原发肺癌向继发转移的分子变化，特别是CTCs在循环中存活的机制，我们对5例进展性转移性非小细胞肺癌患者的正常肺、原发肿瘤和相应的脑转移进行了全基因组测序(WGS)。我们还从转移性癌症患者中分离了CTCs，并对它们进行了全基因组扩增和感兴趣基因的Sanger测序。虽然原发肿瘤显示出与细胞黏附和运动相关的基因突变，但脑转移瘤获得了与细胞应激反应有关的适应性细胞保护基因的突变，如Keap-1、Nrf2和P300，它们是Keap1-Nrf2生存途径的关键参与者。NRF2是一种转录因子，在应激时移位到细胞核，与抗氧化反应元件(ARE)结合，驱动抗氧化基因的表达。已识别的突变影响所有三种蛋白质的调节域，表明在为外周血中的CTCs提供生存优势方面发挥了功能作用，允许它们扩散到远处的器官。
Approximately 90% of all cancer deaths arise from the metastatic spread of primary tumours. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but they are the least well understood at the molecular level. As a barrier to metastasis, cells normally undergo an apoptotic process known as 'anoikis', in circulation. The recent technological advances in the isolation and characterisation of rare circulating tumour cells (CTCs) will allow a better understanding of anoikis resistance. Detailed molecular and functional analyses of anoikis-resistant cells may provide insight into the biology of cancer metastasis and help identify novel targets for prevention of cancer dissemination. To uncover the molecular changes that govern the transition from a primary lung tumour to a secondary metastasis and specifically the mechanisms by which CTCs survive in circulation, we carried out whole genome sequencing (WGS) of normal lung, primary tumours and the corresponding brain metastases from five patients with progressive metastatic non-small-cell lung carcinoma. We also isolated CTCs from patients with metastatic cancer and subjected them to whole genome amplification and Sanger sequencing of genes of interest. While the primary tumours showed mutations in genes associated with cell adhesion and motility, brain metastases acquired mutations in adaptive, cytoprotective genes involved in response to cellular stress such as Keap-1, Nrf2 and P300, which are key players of the Keap1-Nrf2-ARE survival pathway. Nrf2 is a transcriptional factor that upon stress translocates into the nucleus, binds to the anti-oxidant response elements (ARE) and drives the expression of anti-oxidant genes. The identified mutations affect regulatory domains in all three proteins, suggesting a functional role in providing a survival advantage to CTCs in the peripheral blood allowing their dissemination to distant organs.