MOLECULAR GENETIC ALTERATIONS OF ENDOMETRIAL CARCINOMA

子宫内膜癌是女性生殖器最常见的恶性肿瘤。 在美国的大片地区。然而，人们对此知之甚少。 作为发育和发育基础的分子遗传改变 这种常见的恶性肿瘤的进展。分子的线索 子宫内膜癌的发病机制由以下研究提供 结直肠肿瘤的发生。子宫内膜和结直肠肿瘤共有几个 特征包括频繁的K-ras和p53基因突变， 家族性癌症的组织病理学表现和发生 综合征，HNPCC(遗传性非息肉病性结直肠癌)。HNPCC已 最近被发现是由DNA错配修复的突变引起的 基因，hMSH2或hMLH1，导致分子表型特征 由于微卫星序列的不稳定性。微卫星不稳定性 (MI)已在推测为散发性的 子宫内膜癌。分子遗传学研究将用于解决 以下是具体目标： 1)评价子宫内膜癌的诊断价值。以及它的前驱病变。为 通常发生杂合性丢失的染色体区域。全 将评估非顶端着丝粒染色体臂的丢失 利用所选微卫星座位进行杂合性鉴定 基因组中可能含有在发育过程中重要基因的区域 和子宫内膜癌的进展。 2)评估子宫内膜癌前病变的克隆性和 因为微卫星的不稳定性。子宫内膜增生症的前驱症状 对于子宫内膜癌，将评估克隆性和MI到 确定它们在子宫内膜肿瘤形成过程中何时表现出来。 3)分析已知的MI阳性子宫内膜癌的突变 错配修复基因。MI阳性的子宫内膜癌将是 筛选以确定已知DNA错配修复中可能的突变 基因。如果发现突变，我们将确定它们是否是体细胞突变 或者生殖系。 4)确定可能与MI表型相关的新基因 与子宫内膜癌有关。将使用两种方法来 识别新的基因。其中一个将依赖于DBEST的例程搜索 (表达序列标签数据库)具有已知的错配修复基因 另一种是在酿酒酵母中进行遗传筛选，以确定优势 对微卫星有丝分裂不稳定性的负面影响。 拟议的研究旨在促进对 子宫内膜癌的分子发病机制。了解 导致这种疾病的分子基因改变将提供 开发更有效的诊断/治疗的基础 针对这种影响女性的常见恶性肿瘤的策略。

Endometrial carcinoma is the most common malignancy of the female genital tract in the United States. However, very little is known about the molecular genetic alterations that underlie the development and progression of this common malignancy. Clues to the molecular pathogenesis of endometrial carcinoma have been provided by studies of colorectal tumorigenesis. Endometrial and colorectal tumors share several features including frequent K-ras and p53 gene mutations, histopathological appearance, and occurrence in a familial cancer syndrome, HNPCC (hereditary non-polyposis colorectal cancer). HNPCC has recently been found to be caused by mutations in DNA mismatch repair genes, hMSH2 or hMLH1, resulting in a molecular phenotype characterized by instability of microsatellite sequences. Microsatellite instability (MI) has been identified in a subset (20%) of presumably sporadic endometrial carcinomas. Molecular genetic studies will be used to address the following specific aims: 1) To evaluate endometrial carcinoma. and its precursor lesions. for chromosomal regions that commonly undergo loss of heterozygosity. All non-acrocentric chromosomal arms will be evaluated for loss of heterozygosity using selected microsatellite loci in order to identify regions of the genome that may harbor genes important in the development and progression of endometrial carcinoma. 2) To assess precursor lesions of endometrial carcinoma for clonality and for microsatellite instability. Endometrial hyperplasias, the precursors of endometrial carcinoma, will be evaluated for clonality and for MI to determine when they are manifest during endometrial tumorigenesis. 3) To analyze MI positive endometrial carcinomas for mutations in known mismatch repair genes. The MI positive endometrial carcinomas will be screened to identify possible mutations in the known DNA mismatch repair genes. If mutations are identified we will determine if they are somatic or germline. 4) To identify novel genes that may be responsible for the MI phenotype associated with endometrial carcinoma. Two approaches will be used to identify novel genes. One will rely on routine searching of dbEST (database of Expressed Sequence Tags) with known mismatch repair genes and the other will involve a genetic screen in S. cerevisiae for dominant negative effects on microsatellite mitotic instability. The proposed studies are directed at contributing an understanding to the molecular pathogenesis of endometrial carcinoma. Understanding the molecular genetic alterations responsible for this disease will provide a basis for the development of more effective diagnostic/treatment strategies for this common malignancy affecting women.