Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
Nature. 2012 Sep 27;489(7417):519-25. doi: 10.1038/nature11404. Epub 2012 Sep 9.
Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.
肺鳞状细胞癌是一种常见的肺癌类型，每年导致全球约 40 万人死亡。鳞状细胞肺癌的基因组改变尚未得到全面描述，也没有专门针对其治疗的分子靶向药物。作为癌症基因组图谱的一部分，我们对 178 例肺鳞状细胞癌进行了分析，提供了基因组和表观基因组改变的全面图谱。我们表明，该肿瘤类型的特征是复杂的基因组改变，平均每个肿瘤有 360 个外显子突变、165 个基因组重排和 323 个拷贝数改变片段。我们发现 11 个基因中有统计学上反复出现的突变，包括几乎所有标本中的 TP53 突变。在 HLA-A 类 I 主要组织相容性基因中发现了以前未报道的功能丧失突变。显著改变的途径包括 34%的 NFE2L2 和 KEAP1、44%的鳞状分化基因、47%的磷脂酰肌醇-3-羟激酶途径基因和 72%的肿瘤中的 CDKN2A 和 RB1。我们在大多数肿瘤中确定了一个潜在的治疗靶点，为治疗鳞状细胞肺癌提供了新的研究途径。
