Amplicons in Oral Dysplasia

描述（由申请人提供）：口腔鳞状细胞癌（SCC）患者的5年生存率为40%，是身体所有部位中最差的，并且在过去40年中没有改善。大约90%的口腔鳞状细胞癌之前有临床明显的癌前病变，伴有不同程度的不典型增生（从轻度、中度到重度）。转化为SCC与16%的轻度和55%的中度/重度发育不良相关。提高对口腔鳞状细胞癌进展和肿瘤发生的分子基础的理解，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。我们之前报道过口腔鳞状细胞癌基因组的特征是反复出现的拷贝数变化，包括反复出现的小于3mb的狭窄扩增子(1)。我们最近发现，这些窄扩增子也存在于口腔上皮发育不良中，这表明它们可能是口腔癌进展的早期事件。扩增子将注意力集中在它们所包含的作为促进口腔癌发展的候选癌基因的基因上。在这里，我们将开始分析定位于口腔上皮异常增生和口腔SCC中狭窄扩增子的基因如何促进疾病发展和/或进展，重点关注我们发现存在于口腔上皮异常增生和口腔SCC中的三个扩增子，包括定位于2q11的新扩增子，11q22的扩增子包含候选癌基因BIRC2， YAP1和MMP7，以及20p12.2的扩增子包含候选癌基因JAG1。我们将首先评估定位到新型2q11扩增子的基因，以确定其作为扩增驱动癌基因的候选性（目的1）。在Aim 2中，我们将确定来自2q11扩增子的最佳候选癌基因以及BIRC2、YAP1、MMP7和JAG1的表达水平在疾病进展过程中是如何改变的，以及它们的表达模式是否预测了发育不良向SCC的进展或转移风险。我们将通过评估这些基因过表达的功能后果来研究这些基因导致口腔癌的可能机制（目的3）。我们还将确定通过阵列CGH测量的非整倍性（即基因组拷贝数改变的部分，FGA）或包括扩增子在内的特定畸变是否可用于识别有癌症进展风险的发育不良患者（目的4）。口腔鳞状细胞癌患者的5年生存率为40%，是身体所有部位中最糟糕的。在改善口腔癌诊断和治疗方面取得进展的最根本途径是阐明随着癌症发展而变得异常的特定基因和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. Approximately 90% of oral SCC are preceded by clinically evident pre cancerous lesions with varying degrees of dysplasia (from mild, to moderate, to severe). Transformation to SCC is associated with 16% of mild and 55% of moderate/severe dysplasia. 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. We have reported previously that oral squamous cell carcinoma genomes are characterized by recurrent copy number changes, including recurrent narrow amplicons spanning < 3 Mb (1). We have recently found that these narrow amplicons are also present in oral epithelial dysplasia, suggesting that they may be early events in oral cancer progression. The amplicons focus attention on the genes they encompass as candidate oncogenes that contribute to oral cancer development. Here, we will begin the analysis of how genes mapping to narrow amplicons in oral epithelial dysplasia and oral SCC contribute to disease development and/or progression by focusing on three amplicons we found to be present in both dysplasia and oral SCC, including a novel amplicon mapping to 2q11, an amplicon at 11q22 encompassing the candidate oncogenes BIRC2, YAP1 and MMP7 and an amplicon at 20p12.2 harboring the candidate oncogene JAG1. We will first assess genes mapping to the novel 2q11 amplicon for their candidacy as driver oncogenes for amplification (Aim 1). In Aim 2, we will determine how expression levels of the best candidate oncogenes from the 2q11 amplicon as well as BIRC2, YAP1, MMP7 and JAG1 are altered during disease progression and whether their expression patterns are predictive of progression of dysplasia to SCC or risk of metastasis. We will investigate possible mechanisms by which these genes contribute to oral cancer by evaluating the functional consequences of their overexpression (Aim 3). We will also determine whether aneuploidy as measured by array CGH (i.e. fraction of the genome at altered copy number, FGA) or specific aberrations including amplicons can be used to identify dysplasia patients at risk for progression to cancer (Aim 4). 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.