Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell. 2012 Sep 14;150(6):1121-34. doi: 10.1016/j.cell.2012.08.024.
We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.
我们报告了 17 例非小细胞肺癌（NSCLC）患者肿瘤和相邻正常组织样本的全基因组和转录组测序结果。我们在编码序列中鉴定出 3726 个点突变和 90 多个插入缺失，吸烟者的突变频率比从不吸烟者高 10 多倍。鉴定出涉及染色质修饰和 DNA 修复途径的基因中的新改变，以及 DACH1、CFTR、RELN、ABCB5 和 HGF。深度数字测序揭示了从不吸烟者和吸烟者中不同的克隆性模式。所有经过验证的 EFGR 和 KRAS 突变都存在于创始克隆中，这表明它们可能在癌症起始中发挥作用。分析显示了 14 种融合，包括 ROS1 和 ALK，以及新型代谢酶。细胞周期和 JAK-STAT 途径在肺癌中发生显著改变，同时还存在 54 个可能用现有药物靶向治疗的潜在靶基因的扰动。
