Characterization of a New 17q Breast/Ovarian Cancer Gene

新 17q 乳腺癌/卵巢癌基因的表征

• 批准号: 6513045
• 负责人: ELIZABETH M. PETTY
• 金额: $ 30.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-08 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513045
• 关键词: athymic mouse; breast neoplasms; chromosome deletion; complementary DNA; gene expression; gene mutation; gene targeting; genetically modified animals; guanosinetriphosphatases; human tissue; laboratory mouse; neoplasm /cancer genetics; ovary neoplasms; retinoid binding proteins; tumor suppressor genes

DESCRIPTION (Investigator's abstract): Despite significant progress made during the past decade in elucidating important molecular mechanisms underlying breast and ovarian cancer, comprehensive knowledge about hypothesized multistep genetic alterations critical in their pathogenesis is lacking. In fact, only a fraction of putative molecular events hypothesized to be important in the common, sporadic malignancies arising from mammary and ovarian epithelial cells have been elucidated. Genome-wide comparative expression analyses and allelic imbalance analyses, as well as functional assays, of breast and ovarian cancers strongly suggest that alterations in additional, as-of-yet unidentified, genes may be critically important. A deeper understanding of the molecular mechanisms underlying tumor initiation and progression in these malignancies is urgently needed to facilitate innovative development of more effective diagnostic, prognostic, and therapeutic modalities to reduce significant disease associated morbidity and mortality. The goal of this proposal is to conclusively identify and functionally characterize a putative tumor suppressor gene important in breast and ovarian (BROV) cancer that we localized to a discrete, < 300 kb. interstitial region of chromosome 17g25. distinct from and distal to BRCA] . Our continued analyses have strongly supported the localization of a critically important BROV gene to this region. To date, we have developed a fine-scale allelic imbalance map, a comprehensive physical map, a partial transcript map, and an evolving genomic sequence map of the region surrounding a common overlapping discrete region of 17q25 loss in breast and ovarian tumors. We have begun analyzing transcripts and putative candidate genes. Interestingly, two genes mapping to the targeted region, MSF and SEC14LI, demonstrate some intriguing evidence suggesting they warrant continued investigation for their involvement in breast and/or ovarian malignancies. To further examine the relevance of these, as well as other, genes in relationship to 17q25 loss in human breast and ovarian cancers we will: 1) Complete a sequence rich detailed transcript map for this region refined by continued deletion mapping and functional assays, 2) Conduct mutational and expression analyses of attractive candidate genes in well-characterized breast and ovarian cancer cell lines and primary tumors, prioritizing further analyses of MSF and SEC14LI, 3) Perform in vitro and in vivo studies to help assess the function(s) of implicated candidate genes, 4) Create and examine appropriate knockout murine models, and/or targeted transgenic models with inactivating alterations, of the implicated 17q25 gene(s) as indicated.

描述（研究者的摘要）：尽管在 过去十年阐明乳房的重要分子机制 和卵巢癌，关于假设多步骤的综合知识 缺乏对其发病机制至关重要的遗传改变。事实上，只需一个 假设分子事件的一小部分被认为是重要的 由乳腺和卵巢上皮细胞引起的常见、散发性恶性肿瘤 已被阐明。全基因组比较表达分析和等位基因 乳腺癌和卵巢癌的不平衡分析以及功能测定 强烈表明额外的、尚未鉴定的基因的改变 可能至关重要。更深入地了解分子机制 这些恶性肿瘤中潜在的肿瘤发生和进展亟待解决 需要促进更有效诊断的创新开发， 减少重大疾病相关的预后和治疗方式 发病率和死亡率。 该提案的目标是最终确定并在功能上 表征在乳腺癌和卵巢中重要的假定肿瘤抑制基因 (BROV) 我们定位到一个离散的、< 300 kb 的癌症。的间隙区域 染色体17g25。与BRCA不同且远离BRCA]。我们的持续分析 强烈支持极其重要的 BROV 基因的定位 这个地区。迄今为止，我们已经开发出精细的等位基因不平衡图谱， 全面的物理图谱、部分转录图谱和进化的基因组图谱 围绕共同重叠离散区域的区域的序列图 乳腺和卵巢肿瘤中 17q25 缺失。我们已经开始分析文字记录 和假定的候选基因。有趣的是，两个基因映射到目标 MSF 和 SEC14LI 展示了一些有趣的证据表明他们 需要继续调查其是否涉及乳腺和/或卵巢 恶性肿瘤。为了进一步检查这些以及其他的相关性， 与人类乳腺癌和卵巢癌 17q25 缺失相关的基因 将： 1) 完成该区域序列丰富的详细转录图谱 通过持续删除图谱和功能分析进行完善，2) 进行 有吸引力的候选基因的突变和表达分析 明确表征的乳腺癌和卵巢癌细胞系和原发性肿瘤， 优先考虑 MSF 和 SEC14LI 的进一步分析，3) 进行体外和体内分析 体内研究有助于评估相关候选基因的功能，4) 创建并检查适当的基因敲除小鼠模型，和/或靶向 具有相关 17q25 失活改变的转基因模型 基因如所示。