Mechanisms of RET/PTC rearrangements in thyroid cancer

甲状腺癌中RET/PTC重排的机制

• 批准号: 6909115
• 负责人: YURI E NIKIFOROV
• 金额: $ 22.22万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909115
• 关键词: DNA damage; age difference; cell nucleus; clinical research; confocal scanning microscopy; enzyme activity; fluorescent in situ hybridization; gene rearrangement; human subject; ionizing radiation; neoplasm /cancer genetics; oncogenes; pediatric neoplasm /cancer; polymerase chain reaction; protein tyrosine kinase; protooncogene; radiation carcinogen; radiation carcinogenesis; radiation genetics; radiation related neoplasm /cancer; thyroid neoplasm

DESCRIPTION: (Scanned from the applicant's abstract) Thyroid cancer is the most common form of solid neoplasms known to be associated with radiation exposure. However, the mechanisms of radiation-induced carcinogenesis are not well understood. The high prevalence of rearrangements of the RET gene has been recently found in post-Chernobyl papillary thyroid carcinomas and in thyroid tumors from patients exposed to therapeutic external radiation. The positions of breakpoints sites in the RET and ELEI genes identified in post-Chemobyl tumors with RETPTC3 rearrangements suggested that these two genes may be aligned across from each other in the nucleus at the time of DNA breaks (Nikiforov et al., Oncogene, 1999). Consistent with this idea, we found that one pair of RET and H4 genes (contributing to RET/PTCI rearrangement) was juxtaposed in 35 percent of inter-phase nuclei of normal thyroid cells. These data suggest that two potentially recombinogenic chromosomal loci may be contiguous to each other in the nucleus predisposing to generation of rearrangement by adjacent double-strand DNA breaks produced by ionizing radiation or other genotoxic agents. The main goal of the current proposal is to explore the role of nuclear architecture and gene proximity in generation of chromosomal rearrangements after radiation exposure. We propose to use two-color FISH and three-dimensional confocal laser-scanning microscopy to determine the frequency of physical proximity of genes, contributing to the major types of RET/PTC rearrangements, in normal human thyroid follicular cells and in other cell lineages. We will establish whether chromosomal organization with respect to these loci is cell-type specific, age-dependent, or varies with cell cycle stage. Any of these parameters could explain in part the high prevalence of thyroid cancer after irradiation, and the higher susceptibility of children. Then, we will expose cultured cells to different doses of ionizing radiation to test directly the relationship between gene proximity and the frequency of radiation-induced RET/PTC rearrangements in vitro. These studies will extend our understanding of the mechanisms of radiation-induced carcinogenesis in the thyroid gland. In addition, they are likely to have importance for a broad range of chromosomal rearrangements found in cancer.

描述：（从申请人的摘要中扫描）甲状腺癌是最多的 已知与辐射暴露有关的固体肿瘤的常见形式。 但是，辐射引起的致癌作用的机制不是很好 理解。 RET基因重排的高度患病率是 最近在切尔诺贝利乳头状甲状腺癌和甲状腺中发现了 暴露于治疗外部辐射的患者的肿瘤。位置 在后甲贝贝鉴定的RET和ELEI基因中的断点位点的位置 具有RETPTC3重排的肿瘤表明这两个基因可能是 DNA断裂时在核中彼此对齐 （Nikiforov等人，Oncogene，1999）。与这个想法一致，我们发现 一对RET和H4基因（导致RET/PTCI重排）为 在正常甲状腺细胞的35％的相之间核中并置。这些 数据表明，两个潜在的重组染色体基因座可能是 在核中彼此连续 通过电离产生的相邻双链DNA断裂的重排 辐射或其他遗传毒性剂。当前建议的主要目标是 探索核结构和基因接近性的作用 辐射暴露后的染色体重排。我们建议使用 两种彩色鱼和三维共聚焦激光扫描显微镜 确定基因物理接近的频率，有助于 主要类型的RET/PTC重排，在正常的人甲状腺卵泡细胞中 并在其他细胞谱系中。我们将确定染色体组织是否 相对于这些基因座，是细胞类型的特异性，与年龄有关，或随着年龄的依赖性或 细胞周期阶段。这些参数中的任何一个都可以部分解释 辐照后甲状腺癌的患病率和较高的敏感性 儿童。然后，我们将使培养的细胞暴露于不同剂量的电离剂量 辐射以直接测试基因接近与 辐射诱导的RET/PTC重排的频率在体外。这些研究 将扩展我们对辐射诱导的机制的理解 甲状腺中的致癌作用。此外，他们可能有 对于在癌症中发现的各种染色体重排的重要性。