MOLECULAR GENETICS OF HUMAN GYNECOLOGIC PATHOLOGY

人类妇科病理学的分子遗传学

• 批准号: 6162149
• 负责人: JAMES C. BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162149
• 关键词: DNA repair; DNA replication; carcinogenesis; carcinoma; colorectal neoplasms; female reproductive system neoplasm; gene mutation; human genetic material tag; human tissue; leiomyoma; molecular genetics; neoplasm /cancer genetics; oncogenes; ovary neoplasms; pathology; uterus neoplasms

Summary of Work: The molecular genetics analysis of neoplastic conditions of the female reproductive organs including endometrial carcinoma, uterine sarcoma, breast carcinoma, uterine leiomyoma, and ovarian carcinoma are under study. Analysis of these cancers, particularly endometrial cancer has defined a subset that have the molecular genetic phenotype of microsatellite instability. Microsatellite instability in individuals with hereditary non polyposis colorectal carcinoma, is the result of inherited alterations in genes involved in DNA mismatch repair. Mutational analysis fails to find alterations of the HNPCC genes in many sporadic endometrial and ovarian carcinomas with microsatellite instability. Several candidate genes (based on sequence similarity to other mismatch repair genes) were analyzed for alterations in these samples. Of these, hMSH3, was found to be altered in several endometrial tumors and cell lines. Introduction of a normal copy of hMSH3 into a hMSH3 mutant cell line restored certain aspects of defective DNA repair and drastically reduced the microsatellite instability in this cell line.Introduction of hMSH6 also restored DNA repair phenotypes indicating that hMSH3 and hMSH6 share partly redundant functions. We have also identified cell lines defective in the hPMS2 mismatch repair gene and complemented its function by cDNA transfection. The hMSH3/hMSH6 and hPMS2 restored cells are being utilized to determine whether there is an interaction between the cell cycle machinery and mismatch repair. The DNA repair process requires cellular arrest at certain stages of the cell cycle known as checkpoints. Current research is focused on understanding how the mismatch repair system coordinates with the cell cycle machinery to stop cell cycle progression and allow repair following exposure to damaging agents. Also under study are regions of allele loss on chromosomes 1, 10 and 14 in endometrial carcinomas. Fine mapping of these regions may lead to the identification of genes involved in endometrial carcinogenesis.

工作总结：肿瘤的分子遗传学分析 包括子宫内膜在内的女性生殖器官的状况 癌，子宫肉瘤，乳腺癌，子宫平滑肌瘤，和 卵巢癌正在研究中。分析这些癌症， 尤其是子宫内膜癌， 微卫星不稳定性的分子遗传表型。 遗传性非息肉病患者的微卫星不稳定性 结肠直肠癌是基因遗传改变的结果， 参与DNA错配修复。 突变分析未能发现 HNPCC基因在许多散发性子宫内膜和卵巢癌中的改变， 微卫星不稳定性 几个候选基因 （基于与其他错配修复基因的序列相似性） 分析这些样本的变化。 其中，hMSH 3被发现 在几种子宫内膜肿瘤和细胞系中发生改变。引入 将hMSH 3正常拷贝导入hMSH 3突变细胞系， 缺陷DNA修复方面，并大大减少了 该细胞系中的微卫星不稳定性。还引入hMSH 6 恢复的DNA修复表型表明hMSH 3和hMSH 6共享 部分冗余功能。我们还发现了有缺陷的细胞系 在hPMS 2错配修复基因中， 转染 hMSH 3/hMSH 6和hPMS 2恢复的细胞被 用于确定细胞之间是否存在相互作用 循环机械和不匹配的修理。 DNA修复过程需要 细胞停滞在细胞周期的某些阶段，称为检查点。 目前的研究集中在理解错配修复是如何 系统与细胞周期机制协调以停止细胞周期 并允许在暴露于破坏性物质后进行修复。 也 正在研究的是在染色体1，10和14上的等位基因丢失区域， 子宫内膜癌 这些区域的精细映射可能导致 子宫内膜癌发生相关基因的鉴定。