CHROMOSOME BREAKPOINTS, RENAL & SMALL CELL LUNG CANCER

染色体断点，肾脏

• 批准号: 2748717
• 负责人: David I Smith
• 金额: $ 28.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2748717
• 关键词: DNA binding protein; aphidicolin; breast neoplasms; chromosome deletion; chromosome translocation; chromosome walking; cytogenetics; gene rearrangement; genetic library; genetic mapping; genetic markers; head /neck neoplasm; human genetic material tag; kidney neoplasms; molecular cloning; molecular oncology; neoplasm /cancer genetics; northern blottings; nucleic acid hybridization; nucleic acid sequence; polymerase chain reaction; pulsed field gel electrophoresis; small cell lung cancer; southern blotting; tissue /cell culture

DESCRIPTION (Adapted from the Investigator's Abstract): FRA3B, at chromosomal band 3p14.2, is the most active common fragile site in the human genome. This fragile site lies within a chromosomal region frequently deleted in many solid tumors and very close to a translocation breakpoint observed in a family with inherited predisposition to renal cell carcinoma (RCC). In the last 8 years of funding on this project we have generated thousands of chromosome 3-specific cosmids, used these cosmids to assist in the cloning of several chromosome 3p translocation breakpoints, generated a large number of somatic cell hybrids with aphidicolin-induced breakage and localized each of the breakpoints including 17 within FRA3B. We have utilized a 1330 Kb YAC clone which crosses the familial RCC breakpoint and FRA3B to construct a 350 Kb cosmid contig from the RCC breakpoint presumably through all of FRA3B. The 17 aphidicolin-induced breakpoints within 3p14.2 were localized to two tight clusters, one 100 Kb and the other 300 Kb distal to the familial RCC breakpoint. We are proposing to continue and extend these studies to understand the molecular structure of FRA3B and determine why this region is particularly sensitive to aphidicolin. We will also characterize a large number of RCC's, squamous cell carcinomas of the head and neck, lung and breast cancers for chromosome 3p breakage using precisely localized highly polymorphic PCR-amplifiable markers. There are three specific aims of this competing renewal: (1) The molecular characterization of FRA3B; (2) The determination of proteins that bind to FRA3B sequences; and (3) The determination of chromosome 3p breakpoints in RCC, squamous cell carcinoma of the head and neck, and lung and breast cancer. This work will enable us to determine a potentially novel mechanism of chromosomal fragility distinct from expansion of a trinucleotide repeat. This work will also compare chromosome 3p breakpoints induced by aphidicolin to chromosome 3p breakpoints occurring in vivo in cancer patients. Thus this work should help determine the role that FRA3B plays in chromosome breakage and loss in solid tumors.

描述（改编自研究者摘要）：FRA 3B， 染色体带3p14.2，是人类最活跃的常见脆性位点 基因组 这个脆弱的部位通常位于染色体区域内， 在许多实体瘤中缺失并且非常接近易位断裂点 在一个有肾细胞癌遗传倾向的家族中观察到 （RCC）。 在过去的8年里，我们为这个项目提供了资金， 数以千计的3号染色体特异性的互补链，使用这些互补链来帮助 克隆了几个染色体3 p易位断裂点，产生了一个 大量的体细胞杂种与aphidicolin诱导的断裂， 定位每个断点，包括FRA 3B内的17个断点。 我们有 利用1330 Kb YAC克隆，其跨越家族性RCC断裂点， FRA 3B从RCC断裂点构建350 Kb粘粒重叠群，推测 通过FRA 3B。 3p14.2内的17个aphidicolin诱导的断裂点 定位于两个紧密的集群，一个100 Kb，另一个300 Kb的远端 家族性肾细胞癌突变点 我们建议继续并延长 这些研究旨在了解FRA 3B的分子结构， 为什么这个区域对蚜虫菌素特别敏感 我们还将 以大量的肾细胞癌为特征， 和颈部，肺癌和乳腺癌的染色体3 p断裂， 定位的高度多态的PCR可扩增标记。 有三 这种竞争性更新的具体目标：（1）分子表征 （2）确定与FRA 3B序列结合的蛋白质; （3）肾细胞癌、鳞状细胞癌和正常人染色体3 p断裂点的测定 头颈癌、肺癌和乳腺癌。 这项工作将 使我们能够确定一个潜在的新机制，染色体 与三核苷酸重复扩增不同的脆弱性。 这项工作将 并比较了蚜虫菌素诱导的染色体3 p断裂点与染色体3 p断裂点的差异 在癌症患者体内发生的3 p断裂点。 因此，这项工作应 有助于确定FRA 3B在染色体断裂和丢失中的作用， 实体瘤