【Nature】对肺癌发病机制的全面分析或可帮助开发新型的抗癌疗法


近日,刊登在国际杂志Nature上的一篇研究论文中,来自华盛顿大学的研究人员在对常见肺癌的研究中发现,细胞信号路径中突变或许在肺癌肿瘤形成过程中发挥着重要作用,该研究或许为开发新型治疗肺癌的靶向疗法提供一定的研究思路和依据。

肿瘤学家Ramaswamy Govindan博士表示,这项研究中我们首次在基因组学层面从全景角度对许多肺部肿瘤样本进行了分析研究,许多研究都表明肺癌是一种非常异质性的疾病(heterogeneous disease)。结合之前研究者对患肺鳞状细胞癌的178名患者进行研究的数据,本文中研究者公布了他们对400名肺癌患者的研究数据,而且研究者也在不断努力争取分析600例以上的患者数据。

本文研究中,研究者发现大约75%的样本都存在一种突变,即名为RTK/RAS/RAF的路径发生了过度表达的情况,RTK/RAS/RAF路径在肿瘤生长过程中扮演着重要角色。Govindan表示,很明显,RTK/RAS/RAF路径非常重要,该路径突变往往会促进癌细胞的增殖,研究者较为好奇的是到底有多少路径可以被激活。

研究者表示,我们都知道这些肺部肿瘤并不是固定不变的,其也在不断进化之中;因此我们必须进行多种组织切片的研究来判断肿瘤细胞逃逸的机制以及其对疗法的耐受性机制。与此同时研究者也发现了其它重要基因的相关突变,比如EGFR, NF1, NF2和MET基因,在临床研究中也包括对数千名肺癌患者的肿瘤进行筛查来寻找基因EGFR和ALK的改变情况,当外科医生进行手术切除肿瘤后,患者就会被邀请参与临床试验来研究靶向作用这些失调基因的新型药物。

肺癌患者经常会有暴露大量烟草的历史(即抽烟),而抽烟往往会引发一系列的突变,除非研究者对来自成千上万癌症患者的多种样本进行检测,不然他们并不会发现明显的突变。尽管科学家们在理解肺癌的发病机制上已经取得了很大进步,但是本文研究中研究者重点强调,降低肺癌死亡的最佳方法就是帮助个体戒烟。

Comprehensive molecular profiling of lung adenocarcinoma

The Cancer Genome Atlas Research Network

 

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

来源:互联网

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