Genomic scanning for genetic and epigenetic alterations

基因组扫描以检测遗传和表观遗传改变

• 批准号: 6399353
• 负责人: CHRISTOPH PLASS
• 金额: $ 11.03万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399353
• 关键词: DNA methylation; biomarker; chromosomes; gene expression; gene frequency; gene mutation; genetic library; genetic markers; genetic screening; genome; head /neck neoplasm; human genetic material tag; human tissue; loss of heterozygosity; molecular cloning; natural gene amplification; neoplasm /cancer genetics; neoplastic process; oncogenes; oral pharyngeal neoplasm; polymerase chain reaction; restriction mapping; squamous cell carcinoma; tumor suppressor genes; tumor suppressor proteins

Head and Neck cancers (HNC) are the sixth most common cancer in the world, and therefore are a major public health concern. It is now well- established that cancer is a genetic disease at the cellular level. Genetic alterations include the activation of oncogenes and inactivation of tumor suppressor genes. Although substantial progress has been made, still relatively little is known about the genetic mechanisms involved in initiation, progression, and recurrence of these cancers. It is now well accepted that epigenetic alterations (DNA methylation) as well as genetic changes are important for the development of cancer. The importance of DNA methylation in progression of HNCs is not completely understood. To gain a better understanding of the genetic and epigenetic events associated with these events in head and neck squamous cell carcinomas (HNSCC), we propose to identify novel oncogenes and candidate tumor suppressor genes. Our hypothesis is that tumorigenesis of HNSCC is associated with epigenetic changes e.g. promoter methylation, which results in specific changes at the RNA level. We are planning to use the Restriction Landmark Genomic Scanning (RLGS) method which is uniquely suited to identify altered DNA methylation patterns as well as DNA amplification. The goals are: (1) to use RLGS to identify novel amplified sequences and tumor suppressor candidate regions based on altered DNA methylation pattern; (2) the construction of an AscI-EcoRV arrayed library to facilitate the cloning. (3) The cloning of candidate cancer genes will focus on those areas that are altered at high frequency in the tumors. Candidate oncogenes will be identified in chromosomal regions with high incidences of LOH and/pr DNA methylation. (4) The final goal is the establishment of suitable diagnostic biomarkers, which can be used for rapid identification of HNSCC-specific alterations.

头颈癌（HNC）是世界上第六大常见癌症，因此是一个主要的公共卫生问题。癌症是一种细胞水平上的遗传性疾病，这一点已得到公认.遗传改变包括癌基因的激活和肿瘤抑制基因的失活。虽然已经取得了实质性的进展，仍然相对较少的是知道的遗传机制，涉及这些癌症的开始，进展和复发。现在人们普遍认为表观遗传改变（DNA甲基化）以及遗传变化对癌症的发展很重要。DNA甲基化在HNC进展中的重要性尚未完全了解。为了更好地了解头颈部鳞状细胞癌（HNSCC）中与这些事件相关的遗传和表观遗传事件，我们建议鉴定新的癌基因和候选抑癌基因。我们的假设是，HNSCC的肿瘤发生与表观遗传学变化有关，例如启动子甲基化，这导致RNA水平的特异性变化。我们计划使用限制性标志基因组扫描（RLGS）方法，该方法特别适合于识别改变的DNA甲基化模式以及DNA扩增。目标是：（1）利用RLGS技术鉴定新的扩增序列和基于DNA甲基化模式改变的肿瘤抑制基因候选区域;（2）构建AscI-EcoRV阵列文库，便于克隆。(3)候选癌症基因的克隆将集中在肿瘤中高频率改变的区域。将在洛和/pr DNA甲基化发生率高的染色体区域中鉴定候选癌基因。(4)最终目标是建立合适的诊断生物标志物，可用于快速鉴定HNSCC特异性改变。