Amplicons in Oral Dysplasia

口腔发育不良中的扩增子

• 批准号: 7522952
• 负责人: Donna G Albertson
• 金额: $ 27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522952
• 关键词: 11q22; All Sites; Aneuploidy; Apoptosis; Attention; BIRC2 gene; Biopsy; CCND1 gene; Cancerous; Candidate Disease Gene; Cell Line; Chromosomal Loss; Chromosome Mapping; Classification; Clinical; Cultured Cells; DNA; Data; Development; Diagnosis; Disease; Disease Progression; Dysplasia; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelial; Evaluation; Event; Frequencies; Genes; Genetic; Genome; Genomics; Goals; Growth; Intraepithelial Neoplasia; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Measures; Mild Dysplasia; Molecular; Neoplasm Metastasis; Numbers; Oncogenes; Oral; Pathway interactions; Patients; Pattern; Phenotype; Plastics; Play; Premalignant; Prevention therapy; Process; Protein Overexpression; Recurrence; Reporting; Risk; Risk Assessment; Role; Sampling; Severe dysplasia; Squamous cell carcinoma; Survival Rate; Tissues; Tongue Carcinoma; Transcript; Transformed Cell Line; Work; base; cancer risk; expectation; follow-up; gene interaction; human BIRC2 protein; improved; keratinocyte; malignant mouth neoplasm; mouth squamous cell carcinoma; novel; novel strategies; oral cavity epithelium; oral dysplasia; oral premalignancy; tumor; tumor progression; tumorigenesis; tumorigenic

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.

描述(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之一，在过去40年中没有改善。大约90%的口腔鳞状细胞癌前有临床明显的癌前病变，伴有不同程度的不典型增生(从轻度到中度，再到重度)。转化为鳞癌与16%的轻度不典型增生和55%的中/重度不典型增生有关。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。我们以前已经报道过口腔鳞状细胞癌基因组的特征是反复的拷贝数变化，包括反复发生的跨越3Mb(1)的窄扩增。我们最近发现，这些窄扩增也存在于口腔上皮异型增生中，这表明它们可能是口腔癌进展的早期事件。这些扩增物专注于它们作为候选癌基因而包含的基因，这些基因有助于口腔癌的发展。在这里，我们将通过关注我们在口腔异型增生和口腔鳞癌中发现的三个扩增子，开始分析映射到口腔上皮异型增生和口腔鳞癌中的窄扩增片段如何促进疾病的发展和/或进展，包括一个新的定位到2q11的扩增子，一个位于11q22的包含候选癌基因BIRC2、YAP1和MMP7的扩增子，以及一个位于20p12.2的含有候选癌基因JAG1的扩增子。我们将首先评估映射到新的2Q11扩增子的基因作为用于扩增的驱动癌基因的候选(目标1)。在目标2中，我们将确定来自2Q11扩增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如何变化，以及它们的表达模式是否预测不典型增生向鳞癌的进展或转移的风险。我们将通过评估它们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(目标3)。我们还将确定阵列CGH测量的非整倍体(即拷贝数改变的基因组片段，FGA)或包括扩增在内的特定异常是否可用于识别有进展为癌症风险的异型增生患者(目标4)。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。