Amplicons in Oral Dysplasia

口腔发育不良中的扩增子

• 批准号: 7683090
• 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/7683090
• 关键词: 11q22; Aneuploidy; Apoptosis; Attention; BIRC2 gene; Biopsy; CCND1 gene; Cancer Patient; Cancerous; Candidate Disease Gene; Cell Culture Techniques; Cell Line; Chromosomal Loss; Chromosome Mapping; Classification; Clinical; 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 - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Measures; Mild Dysplasia; Molecular; Neoplasm Metastasis; Oncogenes; Oral; Pathway interactions; Patients; Pattern; Phenotype; Plastics; Play; Prevention therapy; Process; Recurrence; Reporting; Risk; Risk Assessment; Role; Sampling; Severe dysplasia; Site; Squamous cell carcinoma; Survival Rate; Tissues; Tongue Carcinoma; Transcript; Transformed Cell Line; Work; base; cancer risk; expectation; follow-up; gene interaction; improved; keratinocyte; malignant mouth neoplasm; mouth squamous cell carcinoma; novel; novel strategies; oral cavity epithelium; oral dysplasia; overexpression; 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（由申请人提供）：40％的口腔鳞状细胞癌（SCC）患者的5年存活率是体内所有部位中最糟糕的，并且在过去40年中没有提高。大约90％的口服SCC之前是临床上明显的癌前病变，其发育不良程度不同（从轻度，到中度到严重）。向SCC的转化与中度/重度发育不良的16％和55％的中性异常有关。对口服SCC进展和肿瘤发生的分子基础的理解有助于发展诊断，癌症风险评估和分类的新策略，以及预防和治疗的靶向疗法。基因组分析特别有用，因为人们普遍认为，口服SCC通过在多步骤过程中的遗传和表观遗传变化而发展。我们先前报道说，口服鳞状细胞癌基因组的特征是复制拷贝数变化，包括跨越<3 Mb的复发窄扩增子（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所包含的基因上，作为候选癌基因，这些癌基因有助于口腔癌的发展。 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和20P12.2的扩增子携带候选癌基因JAG1。我们将首先评估映射到新型2q11扩增子的基因，以候选其作为驱动器癌基因进行扩增的竞选（AIM 1）。在AIM 2中，我们将确定来自2q11扩增子以及BIRC2，YAP1，MMP7和JAG1的最佳候选癌基因的表达水平如何在疾病进展过程中改变，以及它们的表达模式是否可以预测发育不良向SCC的发展或转移风险。我们将研究这些基因通过评估其过表达的功能后果来促进口腔癌的可能机制（AIM 3）。我们还将确定是否通过阵列CGH（即拷贝数变化时的基因组的一部分，FGA）或包括扩增子在内的特定畸变来测量的非整倍性是否可用于识别有癌症进展风险的发育不良患者（AIM 4）。口服鳞状细胞癌患者的5年生存率为40％，在体内所有部位中最差。在改善口腔癌诊断和治疗方面取得进展的最基本方法是阐明特定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。