SEQUENTIAL GENETIC CHANGES DURING TUMOR DEVELOPMENT

肿瘤发展过程中的连续遗传变化

• 批准号: 2442982
• 负责人: Louis Dubeau
• 金额: $ 25.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442982
• 关键词: aneuploidy; athymic mouse; cell line; disease /disorder model; female; flow cytometry; gene deletion mutation; hormone receptor; human tissue; loss of heterozygosity; molecular oncology; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplastic growth; neoplastic transformation; ovary neoplasms; receptor expression; sex chromosomes; steroid hormone receptor; tissue /cell culture; tumor antigens

Ovarian epithelial tumors are subdivided into design (cystadenomas) and malignant (carcinomas) categories. There is also an intermediate entity known as tumors of low malignant potential (LMP). The principal investigator's previous grant focused on identifying frequent molecular genetic differences between these different tumor subtypes in order to obtain insights into the molecular determinants for their phenotypic differences. Recently, the principal investigator's laboratory has succeeded in immortalizing several ovarian cystadenoma cell lines in culture as well as a cell line derived from a LMP tumor. The principal investigator now proposes to pursue studies directed at understanding the molecular genetic determinants of ovarian epithelial tumor development by taking advantage of the above-mentioned cell lines to address the functional significance of specific molecular alterations. Three specific aims are proposed. The first aim will examine the functional significance of expression of steroid and gonadotropin hormone receptors. The levels of expression of such receptors vary among different ovarian tumors and the significance of those differences as well as the potential role of hormone therapy in the management of these tumors is presently unclear. The second specific aim is based on findings from the first grant period that losses of heterozygosity are frequent molecular genetic abnormalities in ovarian carcinomas but are apparently absent in cystadenomas. The principal investigator proposes that the 2 groups of ovarian tumors develop via fundamentally distinct mechanisms and that the presence of loss of heterozygosity, which he regards as a measure of aneuploidy, strongly predisposes to malignant development. The principal investigator will test this hypothesis using 2 different approaches to create mitotic errors in cultured cystadenomas. Such mitotic errors are expected to result in aneuploidy and loss of heterozygosity. The rate of malignant transformation will be compared in treated and control cells. Finally, in the third specific aim, the principal investigator will pursue his recent findings suggesting that a gene which may escape X chromosome inactivation is important for the control of ovarian LMP tumors. This candidate gene will be further localized on the X chromosome and a function for its role in ovarian tumorigenesis may be ascribed to it using microcell-mediated chromosome transfer technologies.

卵巢上皮肿瘤被细分为设计（囊肿）和 恶性（癌）类别。 还有一个中间实体 被称为低恶性势（LMP）的肿瘤。 校长 研究者先前的赠款专注于识别频繁的分子 这些不同的肿瘤亚型之间的遗传差异是为了 获取对其表型的分子决定因素的见解 差异。 最近，主要研究者的实验室已经 成功地使几个卵巢囊肿细胞系永生 培养以及源自LMP肿瘤的细胞系。 校长 研究人员现在建议从事了解理解的研究 卵巢上皮肿瘤发展的分子遗传决定因素 利用上述细胞系来解决 特定分子改变的功能意义。 三个具体 提出了目标。 第一个目标将检查功能意义 类固醇和促性腺激素激素受体的表达。 水平 这种受体的表达在不同的卵巢肿瘤之间各不相同 这些差异的重要性以及 目前尚不清楚这些肿瘤管理中的激素治疗。 第二个特定目的是基于第一赠款期的发现 杂合性的损失是经常出现的分子遗传异常 在卵巢癌中，但在囊肿瘤中显然不存在。 这 首席研究人员建议两组卵巢肿瘤 通过根本不同的机制发展，并且存在 杂合性的丧失，他认为这是针对非整倍性的量度， 强烈倾向于恶性发展。 首席研究员 将使用2种不同的方法来检验这一假设来创建有丝分裂 培养的囊这瘤中的错误。 这种有丝分裂错误有望 导致非整倍性和杂合性丧失。 恶性率 将在处理和对照细胞中比较转化。 最后，在 第三个具体目标，主要研究人员将追求他的最近 发现可能逃脱X染色体灭活的基因 对于控制卵巢LMP肿瘤很重要。 这个候选基因 将进一步定位在X染色体上，其作用的功能 在卵巢肿瘤中，可以使用Microcell介导的 染色体转移技术。