GENETIC ANALYSIS OF OVARIAN CANCER

卵巢癌的基因分析

• 批准号: 2101396
• 负责人: Anne Mary Bowcock
• 金额: $ 24.81万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-04 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101396
• 关键词: brca gene; cancer information system; cancer registry /resource; cancer risk; estrogen receptors; family genetics; gene expression; gene mutation; genetic mapping; genetic markers; genotype; histochemistry /cytochemistry; histopathology; human subject; in situ hybridization; karyotype; linkage mapping; loss of heterozygosity; neoplasm /cancer classification /staging; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nucleic acid sequence; ovary neoplasms; progesterone receptors; tumor suppressor genes

Genetic alterations predisposing to ovarian cancer, both among women in high-risk families and among patients in the general population, can be identified by positional cloning; integrating a systematic survey of genetic alterations in tumors, linkage mapping in families, physical mapping of the linked region, and comparison of sequences of candidate genes therein in tumors, patients and controls. We have successfully applied this approach to breast cancer and propose to do the same for ovarian cancer. Families with multiple cases of ovarian cancer will be identified from four cohorts and first tested for linkage to BRCA1. For families with ovarian cancer linked to 17q21, we will determine whether ovarian cancer is associated with different mutations of BRCA1 than is breast cancer; these will be compared with somatic alterations in sporadic ovarian tumors. We will evaluate epidemiologic risk factors that might distinguish ovarian cancer families with disease linked vs not linked to BRCA1. For families with ovarian cancer not linked to 17q21, we will map the critical genes by a genome-wide search, initially focusing on chromosomal regions with imbalance in ovarian tumors, and those with genes linked to predisposition to other forms of cancer also seen in the ovarian cancer families. We will identify candidate regions both from published reports of loss of heterozygosity (LOH), gene amplification, increased modes of gene expression and chromosomal alterations in ovarian tumors, and by screening malignant and benign ovarian tumors for LOH on all chromosome arms and karyotyping incident cases. The patterns of acquired mutations leading to ovarian cancer in the general population will be evaluated by identifying mutations at predisposing genes, LOH at critical regions and increased gene amplification and expression of ovarian oncogenes in the tumors of 300 previously identified patients, and 120 patients to be identified over the next four years. Correlations between genetic markers and tumor progression and outcome will also be made. Ovarian cancer is one of the most lethal cancers for women because it has been nearly impossible to detect at early, curable stages. Identifying genes critical to ovarian cancer development and progression, both in high risk families and among women generally, will pave the way for possible prevention, much earlier diagnosis and improved outcome.

基因改变易患卵巢癌，无论是女性还是女性 高危家庭和一般人群的患者中，可以 通过定位克隆鉴定；整合系统调查 肿瘤的遗传改变、家族的连锁图谱、物理 连接区域的作图和候选序列的比较 肿瘤、患者和对照中的基因。我们已经成功 将这种方法应用于乳腺癌，并建议对乳腺癌采取同样的方法 卵巢癌。患有多例卵巢癌的家庭将 从四个队列中鉴定出来，并首先测试与 BRCA1 的关联。 为了 患有与 17q21 相关的卵巢癌的家族，我们将确定是否 卵巢癌与 BRCA1 突变的相关性不同于卵巢癌 乳腺癌;这些将与零星的体细胞改变进行比较 卵巢肿瘤。我们将评估可能的流行病学危险因素 区分与疾病相关的卵巢癌家族和与疾病无关的卵巢癌家族 乳腺癌1。 对于与 17q21 无关的卵巢癌家族，我们将绘制 通过全基因组搜索来寻找关键基因，最初侧重于染色体 卵巢肿瘤不平衡的区域，以及具有相关基因的区域 卵巢癌中也存在其他形式癌症的易感性 家庭。 我们将从已发布的报告中确定候选区域 杂合性丢失（LOH）、基因扩增、增加模式 卵巢肿瘤中的基因表达和染色体改变，以及 筛查恶性和良性卵巢肿瘤所有染色体上的 LOH 武器和核型分析事件案例。 导致卵巢癌的获得性突变模式 将通过识别突变来评估一般人群 易感基因、关键区域的LOH和增加的基因 300个肿瘤中卵巢癌基因的扩增和表达 先前确定的患者，以及 120 名患者 未来四年。遗传标记与肿瘤的相关性 也将取得进展和成果。卵巢癌是其中之一 对女性来说最致命的癌症，因为几乎不可能 在早期、可治愈的阶段进行检测。识别对卵巢至关重要的基因 癌症的发生和进展，无论是在高风险家庭还是在 一般来说，女性会更早地为可能的预防铺平道路 诊断和改善结果。