CHROMOSOME BREAKPOINTS, RENAL & SMALL CELL LUNG CANCER

染色体断点，肾脏

• 批准号: 2894780
• 负责人: David I Smith
• 金额: $ 27.26万
• 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/2894780
• 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（改编自研究者的摘要）：FRA3B，位于 染色体带3p14.2，是人类最活跃的常见脆弱位点 基因组。 这个脆弱的位点经常位于染色体区域内 在许多实体瘤中被删除并且非常接近易位断点 在具有肾细胞癌遗传倾向的家族中观察到 （RCC）。 在过去 8 年中，我们为该项目筹集了资金 数千个 3 号染色体特异性粘粒，使用这些粘粒来协助 几个染色体3p易位断点的克隆，产生了 大量体细胞杂种与阿非迪霉素诱导的断裂和 定位了每个断点，包括 FRA3B 中的 17 个断点。 我们有 利用跨越家族 RCC 断点的 1330 Kb YAC 克隆 FRA3B 可能从 RCC 断点构建 350 Kb 粘粒重叠群 通过所有 FRA3B。 3p14.2 内 17 个由 aphidicolin 诱导的断点 定位于两个紧密的簇，一个 100 Kb，另一个 300 Kb 远端 到家族性 RCC 断点。 我们建议继续并延长 这些研究旨在了解 FRA3B 的分子结构并确定 为什么这个区域对阿菲迪霉素特别敏感。 我们还将 表征大量 RCC、头部鳞状细胞癌 以及颈癌、肺癌和乳腺癌的染色体 3p 断裂，精确使用 局部高度多态性 PCR 扩增标记。 有三个 这种竞争性更新的具体目标：（1）分子表征 FRA3B； (2) 与FRA3B序列结合的蛋白质的测定； (3)肾细胞癌、鳞状细胞染色体3p断点的测定 头颈癌、肺癌和乳腺癌。 这项工作将 使我们能够确定染色体的潜在新机制 脆性与三核苷酸重复的扩展不同。 这项工作将 还比较了 aphidicolin 诱导的染色体 3p 断点与染色体 癌症患者体内发生的 3p 断点。 因此这项工作应该 帮助确定 FRA3B 在染色体断裂和丢失中所起的作用 实体瘤。