Genomic and Functional Analysis of Oral Cancer Development

描述(申请人提供)：口腔鳞状细胞癌(SCC)患者的5年存活率为40%，是身体所有部位中最差的之一，在过去40年中没有改善。更好地了解口腔鳞状细胞癌进展和肿瘤发生的分子基础有助于开发新的诊断策略、癌症风险评估和分类以及预防和治疗的靶向治疗。基因组分析特别有用，因为人们普遍认为口腔鳞状细胞癌是通过在多步骤过程中遗传和表观遗传变化的积累而发展起来的。我们实验室最近的工作发现，口腔鳞状细胞癌基因组的特征是重复的拷贝数变化，包括重复的跨越3Mb的窄扩增(1)。这些扩增集中在它们作为候选癌基因而包含的基因上，这些基因有助于口腔癌的发展。此外，在口腔上皮异型增生中也观察到了许多这样的扩增子，这是一种癌前状态，通常先于癌症的发展。因此，在这种特殊的肿瘤类型中，似乎是扩增子向对这种疾病的发展至关重要的基因发出信号。在这里，我们将集中于三个与口腔癌有关的候选癌基因的进一步分析，因为它们或它们的遗传网络成员被映射到口腔鳞癌中的一个狭窄扩增子上。我们将调查这些基因在疾病进展过程中何时何地表达(目标1)。在目标2中，我们将研究它们如何，即通过什么机制，促进癌症的发展(例如，鳞状上皮生长和分化的改变，转移等)。此外，我们将评估阵列CGH检测到的基因组异常预测癌前病变进展为癌症的能力。 口腔鳞状细胞癌患者的5年存活率为40%，是身体所有部位中最差的。在改善口腔癌的诊断和治疗方面取得进展的最根本的方法是阐明特定的基因以及随着癌症的发展而变得异常的基因之间的相互作用。

DESCRIPTION (provided by applicant): The 5-year survival rate for patients with oral squamous cell carcinoma (SCC), at 40%, is among the worst of all sites in the body and has not improved over the past 40 years. Improved understanding of the molecular basis of oral SCC progression and tumorigenesis can contribute to development of novel strategies for diagnosis, cancer risk assessment and classification, as well as targeted therapies for prevention and treatment. Genomic analysis is of particular utility, since it is generally accepted that oral SCC develop via accumulation of genetic and epigenetic changes in a multi-step process. Recent work in our laboratory found that oral squamous cell carcinoma genomes are characterized by recurrent copy number changes, including recurrent narrow amplicons spanning < 3 Mb (1). These amplicons focus attention on the genes they encompass as candidate oncogenes that contribute to oral cancer development. Moreover, a number of these amplicons have also been observed in oral epithelial dysplasia, a pre-malignant condition which frequently precedes cancer development. Thus, in this particular tumor type, it appears that amplicons signal genes important for the development of this disease. Here we will focus on further analysis of three candidate oncogenes implicated in oral cancer because they, or members of their genetic network, mapped to a narrow amplicon in oral SCC. We will investigate when and where these genes are expressed during disease progression (Aim 1). In Aim 2, we will investigate how, i.e. by what mechanism, they contribute to cancer development (e.g. alterations in growth and differentiation of the squamous epithelium, metastasis, etc.). In addition, we will evaluate the capability of genomic aberrations detected by array CGH to predict progression of pre-malignant lesions to cancer. The 5-year survival rate for patients with oral squamous cell carcinoma is 40%, among the worst of all sites in the body. The most fundamental way to make progress toward improving diagnosis and treatment of oral cancer is to elucidate the specific genes and the interactions among genes that become abnormal as cancer develops.