MOLECULAR GENETICS OF HUMAN GYNECOLOGIC PATHOLOGY

人类妇科病理学的分子遗传学

• 批准号: 2574317
• 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/2574317
• 关键词: DNA repair; DNA replication; carcinogenesis; carcinoma; cell cycle; colorectal neoplasms; disease /disorder proneness /risk; female reproductive system neoplasm; gene mutation; human genetic material tag; leiomyoma; molecular oncology; neoplasm /cancer genetics; oncogenes; ovary neoplasms; uterus neoplasms

The molecular genetics analysis of neoplastic conditions of the female genital tract including emdometrial carcinoma, uterine sarcoma, uterine leiomyoma and ovarian carcinoma are under study. Significant progress has been achieved in defining the molecular genetic basis of these tumors. 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 andovarian 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 micro-satellite instability in this cell line. These results indicate that additional genes function to maintain the fidelity of replication and that hMSH3 plays a key role in this process. In addition studies are underway to determine whether there is an interaction between the cell cycle machinery and mismatch repair. The DNA repair process requires a 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.

女性恶性肿瘤的分子遗传学分析 生殖道包括子宫内膜癌、子宫肉瘤、子宫 平滑肌瘤和卵巢癌正在研究中。重大进展 在确定这些肿瘤的分子遗传基础方面取得了进展。 对这些癌症，特别是子宫内膜癌的分析已经确定了 具有微卫星分子遗传表型的亚类 不稳定 微卫星不稳定性在遗传性 非息肉病性结直肠癌，是遗传的结果， 参与DNA错配修复的基因改变。 突变 分析未能发现HNPCC基因的改变，在许多散发性 微卫星不稳定性的子宫内膜和卵巢癌 几个候选基因（基于与其他错配的序列相似性） 修复基因）分析这些样品中的改变。 其中， hMSH3在一些子宫内膜肿瘤和子宫内膜癌细胞中被发现改变。 线将正常拷贝的hMSH3导入hMSH3突变细胞 线恢复了缺陷DNA修复的某些方面， 降低了该细胞系中微卫星的不稳定性。这些结果 表明另外的基因起着维持 hMSH3在这一过程中起着关键作用。 此外 研究正在进行中，以确定是否有相互作用， 细胞周期机制和错配修复 DNA修复过程 需要在细胞周期的某些阶段发生细胞停滞，即 检查站 目前的研究重点是了解 错配修复系统与细胞周期机制协调， 细胞周期进展，并允许在暴露于损伤后进行修复 剂.