Comprehensive molecular profiling of lung adenocarcinoma.
Comprehensive molecular profiling of lung adenocarcinoma.
复制标题
DOI：
10.1038/nature13385
复制
发表时间：
2014-07-31
期刊：
影响因子：
64.8
通讯作者：
Cancer Genome Atlas Research Network
中科院分区：
文献类型：
--
作者：
Cancer Genome Atlas Research Network
肺腺癌是全世界癌症死亡的主要原因。在这里，我们报告了230例切除的肺腺癌的分子概况，使用信使RNA，microRNA和DNA测序结合拷贝数，甲基化和蛋白质组学分析。体细胞突变率很高（平均每兆碱基8.9个突变）。18个基因发生了统计学显著突变，包括RIT 1激活突变和新描述的功能丧失MGA突变，这些突变与局灶性MYC扩增相互排斥。EGFR突变在女性患者中更常见，而RBM10突变在男性中更常见。13%的病例中出现NF 1、MET、ERBB 2和RIT 1的畸变，并且在其他缺乏活化癌基因的样本中富集，表明这些事件在某些肿瘤中起驱动作用。来自同一肿瘤的DNA和mRNA序列突出显示了由体细胞基因组变化驱动的剪接改变，包括4%病例中MET mRNA的外显子14跳跃。MAPK和PI（3）K通路活性，当在蛋白质水平上测量时，仅在一小部分病例中通过已知的突变来解释，这表明了通路激活的额外的、无法解释的机制。这些数据为肺腺癌的分类和进一步研究肺腺癌的分子发病机制奠定了基础。
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.