ISOLATION CHROMOSOME 17Q25 GENE INVOLED IN BREAST CANCER

与乳腺癌有关的 17Q25 染色体分离基因

• 批准号: 2390865
• 负责人: ELIZABETH M. PETTY
• 金额: $ 9.07万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-07 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2390865
• 关键词: artificial chromosomes; brca gene; breast neoplasms; cellular oncology; chromosome translocation; complementary DNA; cytogenetics; female; gene expression; gene mutation; genetic mapping; genetic markers; genetic polymorphism; human tissue; loss of heterozygosity; molecular cloning; neoplasm /cancer genetics; neoplastic process; northern blottings; nucleic acid hybridization; nucleic acid sequence; pathologic process; polymerase chain reaction; tumor suppressor genes; women's health

RESEARCH PROPOSAL: Breast cancer rivals lung cancer as one of the leading causes of morbidity and mortality in U.S. women, accounting for approximately 25% of their cancer deaths. Significant progress has been made in understanding the genetics of breast cancer including the recent identification of a critical tumor suppressor gene, BRCA1. Other genes, including TP53 and MTS1, have demonstrated involvement in breast carcinogenesis. In general, cancer arises from cells that escape normal growth regulation enabling them to proliferate rapidly, invade locally and metastasize to distant sites. Genetic study of colorectal cancer has shown that tumorigenesis is the result of a multistep molecular process involving both the activation of protooncogenes and inactivation of tumor suppressor genes. Both gene amplification and loss of heterozygosity (LOH) studies support the hypothesis that alterations in multiple interacting growth-regulatory genes are critical in breast carcinogenesis. Characterization of all these alterations is necessary to understand their interrelated roles in breast cancer and to ultimately facilitate improved medical management of breast cancer for all women. The goal of this research is to isolate a putative breast cancer gene which has been recently localized to chromosome 17q25 (distal to BRCA1) by LOH and cytogenetic studies. The specific aims are to: 1) Define the smallest region of LOH on 17q25 by analysis of matched tumor and normal tissue with existing and newly developed highly polymorphic microsatellite markers 2) Analyze non-random 17q25 cytogenetic translocation breakpoints in breast carcinomas 3) Construct a YAC/P1 contig spanning the smallest region of LOH 4) Isolate expressed DNA sequences from this interval and 5) Elucidate this gene's role in breast cancer.

研究提案：乳腺癌可与肺癌媲美，成为主要癌症之一 美国妇女发病和死亡的原因，占 大约 25% 的癌症死亡。已取得重大进展 旨在了解乳腺癌的遗传学，包括最近的研究 鉴定出关键的肿瘤抑制基因 BRCA1。其他基因， 包括 TP53 和 MTS1，已证明参与乳腺 致癌作用。一般来说，癌症是由逃离正常细胞的细胞产生的。 生长调节使它们能够迅速增殖、侵入局部并 转移到远处的部位。结直肠癌的基因研究表明 肿瘤发生是多步骤分子过程的结果 涉及原癌基因的激活和肿瘤的灭活 抑制基因。基因扩增和杂合性丢失 (LOH) 研究支持这样的假设：多重相互作用的改变 生长调节基因在乳腺癌发生中至关重要。 所有这些改变的特征对于理解它们是必要的 乳腺癌中相互关联的作用，并最终促进改善 对所有女性进行乳腺癌的医疗管理。此举的目标 研究目的是分离出一种假定的乳腺癌基因，该基因已被 最近通过 LOH 定位于染色体 17q25（BRCA1 远端） 细胞遗传学研究。具体目标是： 1）定义最小 通过对匹配的肿瘤和正常组织进行分析，确定 17q25 上的 LOH 区域 现有和新开发的高度多态性微卫星标记2) 分析乳腺非随机 17q25 细胞遗传学易位断点 癌 3) 构建跨越最小区域的 YAC/P1 重叠群 LOH 4) 从该区间分离表达的 DNA 序列并 5) 阐明 该基因在乳腺癌中的作用。