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SCC之前有临床上明显的癌前病变，具有不同程度的发育不良（从轻度到中度，再到重度）。转化为SCC与16%的轻度和55%的中度/重度异型增生相关。提高对口腔SCC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。基因组分析是特别有用的，因为它被普遍接受，口腔鳞状细胞癌的发展，通过积累的遗传和表观遗传的变化，在一个多步骤的过程。我们以前曾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，包括反复出现的窄扩增子跨度< 3 Mb（1）。我们最近发现这些狭窄的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作为有助于口腔癌发展的候选癌基因所包含的基因上。在这里，我们将开始分析定位到口腔上皮异型增生和口腔SCC中狭窄扩增子的基因如何通过关注我们发现存在于异型增生和口腔SCC中的三种扩增子来促进疾病的发展和/或进展，包括定位到2 q11的新扩增子，包含候选癌基因BIRC 2的11 q22扩增子，YAP 1和MMP 7以及20 p12.2处的携带候选癌基因JAG 1的扩增子。我们将首先评估定位到新的2 q11扩增子的基因作为扩增驱动癌基因的候选资格（目的1）。在目标2中，我们将确定来自2 q11扩增子以及BIRC 2，YAP 1，MMP 7和JAG 1的最佳候选癌基因的表达水平在疾病进展过程中如何改变，以及它们的表达模式是否可预测异型增生向SCC的进展或转移的风险。我们将通过评估这些基因过度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（即拷贝数改变的基因组分数，FGA）或特定畸变（包括扩增子）测量的非整倍性是否可用于识别有进展为癌症风险的发育不良患者（目标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差的。要想提高口腔癌的诊断和治疗水平，最根本的方法是阐明特定的基因以及随着癌症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. 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.