CHROMOSOME BREAKPOINTS, RENAL & SMALL CELL LUNG CANCER

说明(改编自《调查者摘要》)：FRA3B，见 染色体带3p14.2是人类最活跃的常见脆性部位 基因组。这种脆弱部位通常位于染色体区域内。 在许多实体瘤中缺失，非常接近易位断点 在一个遗传性肾癌易感家系中观察 (RCC)。在过去8年对这个项目的资助中，我们产生了 数以千计的染色体3特定的宇宙体，使用这些宇宙体来帮助 克隆了几个染色体3p易位断裂点，产生了 大量的体细胞杂交种与蜂毒灵诱导的破裂和 本地化了每个断点，包括FRA3B内的17个断点。我们有 利用了跨越家族RCC断点的1330 KB YAC克隆 FRA3B可能从RCC断点构建一个350 kb的粘粒重叠群 通过整个法兰克福机场3B。3p14.2内的17个蚜菌素诱导的断裂点 定位到两个紧密的群集，一个是100 KB，另一个是300 KB远端 家族性RCC断点。我们建议继续和延长 这些研究旨在了解FRA3B的分子结构并确定 为什么这一区域对蜂毒灵特别敏感。我们还将 大量的肾癌，头部鳞状细胞癌的特征 和颈部、肺癌和乳腺癌的染色体3p断裂使用精确 定位的高度多态的聚合酶链式反应可扩增标记。一共有三个 这一竞争更新的具体目标：(1)分子表征 FRA3B；(2)与FRA3B序列结合的蛋白质； (3)肾鳞状细胞癌中染色体3p断裂点的测定 头颈癌、肺癌和乳腺癌。这项工作将 使我们能够确定一种潜在的新的染色体机制 脆弱性不同于三核苷酸重复序列的扩张。这项工作将 此外，还比较了蜂毒灵诱导的染色体3p断裂点与染色体。 3P断裂点在癌症患者体内发生。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。

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.