17Q25 BREAST CANCER GENE--ISOLATION AND ANALYSIS

17Q25乳腺癌基因--分离与分析

基本信息

批准号：
2769910
负责人：
ELIZABETH M. PETTY
金额：
$ 21.11万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-08 至 2000-08-31
项目状态：
已结题

项目摘要

Despite laudable recent progress in the identification of key genetic events crucial to inherited breast carcinogenesis, there is a clear lack of understanding regarding the widely hypothesized multi-step genetic events that are critical in the initiation and progression of this common, most often sporadic, and sometimes fatal cancer. Genetic analysis of sporadic breast tumors, including genome wide gene amplificationand loss of heterozygosity (LOH) studies, strongly supports the hypothesis that alterations in multiple interacting growth regulatory genes are critical in breast carcinogenesis. Characterization of the various specific alterations is necessary to understand their interrelated roles in breast carcinogenesis and their potential roles in other solid tumor malignancies. A greater understanding of the molecular basis of cancer iwll ultimately facilitate improved medical management of the disease. Specifically, increased understanding of critical genetic mechanisms should lead to improved diagnostic testing, prognostic testing, prognostic testing, and development of effective therapeutic modalities. The chief goal of this research proposal is to characterize a putative tumor suppressor gene that has been localized to a 3 cM interstitial region of chromosome 17q. Distal to and distinct from BRCA1, by tumor deletion mapping of sporadic breast tumors in our laboratory. Our hypothesis is that this putative 17q25 gene may act as a tumor suppressor in the progression of sporadic invasive ductal carcinomas. Functional analyses of mammary carcinomas by others have demonstrated that transfection of 17q25 and 17p material into a wild type p53 breast cancer cell line alters the growth and phenotype of the cell line and negates tumorigenicity in mice. Non-random cytogenetic translocations of 17q25 have also been identified in primary breast tumors. Additional studies have demonstrated that this region of chromosome 17 may also harbor a gene(s) involved in other solid tumors including ovarian and esophageal neoplasms. Our continued efforts to isolate and characterize the putative gene(s) will focus on: 1) Continued fine tumor deletion mapping studies both in breast tumors and other tumor types, 2) Linkage analysis of this genetic region in non-BRCA1 or -BRCA2 breast cancer kindreds, 3) Construction of a physical map with development of a YAC/P1/cosmid contig spanning the smallest region containing the putative tumor suppressor gene, 4) Isolation of candidate gene sequences using a variety of strategies including exon amplificatin techniques and direct cDNA selection methods, and 5) Analysis of candidate genes and elucidation of their role in breast carcinogenesis.

尽管最近在确定关键因素方面取得了值得称赞的进展遗传事件对遗传性乳腺癌至关重要，有一个对广泛的假设显然缺乏理解多步骤遗传事件对于启动和发生至关重要这种常见的、最常见的是散发性的、有时是偶发性的进展致命的癌症。散发性乳腺肿瘤的遗传分析，包括全基因组基因扩增和杂合性丢失 (LOH) 研究强烈支持了这样的假设：多种变化相互作用的生长调节基因对于乳房至关重要致癌作用。各种具体改变的表征有必要了解它们在乳房中相互关联的作用致癌作用及其在其他实体瘤中的潜在作用恶性肿瘤。对分子基础有了更深入的了解癌症 iwill 最终促进改善医疗管理这种疾病。具体来说，增加对关键遗传的了解机制应导致改进的诊断测试、预后测试、预后测试和开发有效的治疗方式。本研究计划的主要目标是描述假定的肿瘤抑制基因已定位于 3 cM 17q 染色体间质区。远端且不同于 BRCA1，通过对散发性乳腺肿瘤进行肿瘤缺失图谱分析我们的实验室。我们的假设是这个假定的 17q25 基因可能在散发性肿瘤的进展中充当肿瘤抑制因子浸润性导管癌。乳腺功能分析其他人的癌症研究表明，17q25 的转染和 17p 材料进入野生型 p53 乳腺癌细胞系会发生变化细胞系的生长和表型并否定小鼠的致瘤性。非随机细胞遗传学易位 17q25 也在原发性乳腺肿瘤中被发现。其他研究表明，该区域 17号染色体也可能含有参与其他固体的基因肿瘤包括卵巢肿瘤和食管肿瘤。我们的继续努力分离和表征推定基因将重点关注：1）持续精细肿瘤缺失图谱研究在乳腺肿瘤和其他肿瘤类型中，2) 连锁分析非 BRCA1 或 -BRCA2 乳腺癌中该基因区域的亲属，3）通过开发构建物理地图 YAC/P1/粘粒重叠群跨越包含假定的抑癌基因，4)候选基因的分离使用多种策略（包括外显子扩增）的序列技术和直接 cDNA 选择方法，以及 5) 分析候选基因及其在乳腺中的作用的阐明致癌作用。