The dynamics of gene expression changes in a mouse model of oral tumorigenesis may help refine prevention and treatment strategies in patients with oral cancer
The dynamics of gene expression changes in a mouse model of oral tumorigenesis may help refine prevention and treatment strategies in patients with oral cancer
复制标题
DOI：
10.18632/oncotarget.8321
复制
发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Saintigny, Pierre
中科院分区：
文献类型：
--
作者：
Foy, Jean-Philippe;Tortereau, Antonin;Saintigny, Pierre
更好地了解口腔肿瘤发生早期发生的分子变化的动力学可能有助于完善预防和治疗策略。我们从4-NQO口腔肿瘤小鼠模型中获得了微解剖正常粘膜、增生、不典型增生和肿瘤的全基因组表达谱。肿瘤与正常粘膜之间差异表达的基因定义了“肿瘤基因集”（tumor gene set， TGS），包括4个不重叠的基因亚群，这些基因亚群表征了不同疾病进展阶段基因表达变化的动态。大多数基因表达变化发生在早期或进行性。这些小鼠基因组与人类疾病的相关性在多个数据集中进行了测试，包括TCGA和癌症药物敏感性基因组学项目。TGS能够在3个独立的数据集中区分口腔鳞状细胞癌（OSCC）和正常口腔黏膜。在小鼠TGS富集的OSCC样品中，CASP8突变频率高，11q13.3扩增，PIK3CA突变频率低。在4-NQO模型中观察到的早期变化与口腔肿瘤前病变患者的口腔无癌生存期较短的趋势相关，这在多变量分析中未见。在51个消化道鳞状细胞癌细胞系中，4- nqo模型中观察到的进行性变化与对4种不同MEK抑制剂的敏感性增加有关。总之，4-NQO模型的分子变化动力学表明，MEK抑制可能与预防和治疗特定分子定义的OSCC亚群有关。
A better understanding of the dynamics of molecular changes occurring during the early stages of oral tumorigenesis may help refine prevention and treatment strategies. We generated genome-wide expression profiles of microdissected normal mucosa, hyperplasia, dysplasia and tumors derived from the 4-NQO mouse model of oral tumorigenesis. Genes differentially expressed between tumor and normal mucosa defined the "tumor gene set" (TGS), including 4 non-overlapping gene subsets that characterize the dynamics of gene expression changes through different stages of disease progression. The majority of gene expression changes occurred early or progressively. The relevance of these mouse gene sets to human disease was tested in multiple datasets including the TCGA and the Genomics of Drug Sensitivity in Cancer project. The TGS was able to discriminate oral squamous cell carcinoma (OSCC) from normal oral mucosa in 3 independent datasets. The OSCC samples enriched in the mouse TGS displayed high frequency of CASP8 mutations, 11q13.3 amplifications and low frequency of PIK3CA mutations. Early changes observed in the 4-NQO model were associated with a trend toward a shorter oral cancer-free survival in patients with oral preneoplasia that was not seen in multivariate analysis. Progressive changes observed in the 4-NQO model were associated with an increased sensitivity to 4 different MEK inhibitors in a panel of 51 squamous cell carcinoma cell lines of the areodigestive tract. In conclusion, the dynamics of molecular changes in the 4-NQO model reveal that MEK inhibition may be relevant to prevention and treatment of a specific molecularly-defined subgroup of OSCC.