Lea I A, Jackson M A, Li X, Bailey S, Peddada S D, Dunnick J K
Integrated Laboratory Systems, Inc., Research Triangle Park, NC 27709, USA.
Carcinogenesis. 2007 Sep;28(9):1851-8. doi: 10.1093/carcin/bgm176. Epub 2007 Aug 11.
Cancer is a complex disease that involves the accumulation of both genetic and epigenetic alterations of numerous genes. Data in the Genetic Alterations in Cancer database for gene mutations and allelic loss [loss of heterozygosity (LOH)] in human tumors (e.g. lung, oral, esophagus, stomach and colon/rectum) were reviewed. Results for the genes and pathways implicated in tumor development at these sites are presented. Mutation incidence, spectra and codon specificity are described for lung, larynx and oral tumors. LOH occurred more frequently than gene mutations in tumors from all sites examined. The cell cycle gene, TP53 (all sites), and cell signaling gene, APC (colorectal and gastric cancers), were the only genes with similar incidences of LOH and mutation. Alterations of one or more cell cycle and cell signaling genes were reported for tumors from each site. Site-specific activation was apparent in the cell signaling mitogen-activated protein kinase oncogenes (KRAS in lung, HRAS in oral cancers and BRAF in esophageal and colorectal cancers). Analysis of genetic changes in lung tumors showed that the incidence of mutations in the TP53 and KRAS genes and the incidence of LOH in the FHIT gene were significantly greater in smokers versus non-smokers (P < 0.01). In lung and oral cancers, the TP53 GC --> TA transversion frequency increased with tobacco smoke exposure (P < 0.05). Furthermore, the TP53 mutational hot spots for lung and laryngeal cancers from smokers included codons 157, 245 and 273, whereas for oral tumors included codons 280 and 281.
癌症是一种复杂的疾病，涉及众多基因的遗传和表观遗传改变的积累。我们回顾了癌症基因改变数据库中关于人类肿瘤（如肺癌、口腔癌、食管癌、胃癌和结肠/直肠癌）基因突变和等位基因缺失[杂合性缺失（LOH）]的数据。本文呈现了这些部位肿瘤发生过程中涉及的基因和信号通路的研究结果。文中描述了肺癌、喉癌和口腔癌的基因突变发生率、谱型及密码子特异性。在所研究的所有部位的肿瘤中，LOH的发生频率高于基因突变。细胞周期基因TP53（所有部位）和细胞信号基因APC（结直肠癌和胃癌）是仅有的LOH和突变发生率相似的基因。每个部位的肿瘤均报告了一个或多个细胞周期和细胞信号基因的改变。细胞信号促分裂原活化蛋白激酶癌基因存在位点特异性激活（肺癌中的KRAS、口腔癌中的HRAS以及食管癌和结直肠癌中的BRAF）。肺癌基因变化分析表明，吸烟者中TP53和KRAS基因的突变发生率以及FHIT基因的LOH发生率显著高于非吸烟者（P < 0.01）。在肺癌和口腔癌中，TP53基因GC --> TA颠换频率随烟草烟雾暴露增加（P < 0.05）。此外，吸烟者肺癌和喉癌的TP53突变热点包括密码子157、245和273，而口腔肿瘤的突变热点包括密码子280和281。
