CLONING A UTERINE SEROUS CARCINOMA TUMOR SUPPRESSOR GENE

这项提案的总体目标是克隆一个肿瘤抑制基因 参与了最具侵略性的子宫内膜的发展 子宫乳头状浆液性癌（UPSC）。癌 子宫内膜是美国最常见的妇科恶性肿瘤，与 估计每年有33，000个新病例。 虽然UPSC占 超过10%的子宫内膜癌， 占子宫内膜癌死亡率的一半以上。 UPSC和浆液性 卵巢癌在组织学上难以区分。 它们显示 类似的转移扩散模式，并且已经提出， 子宫内膜和卵巢的浆液性癌起源于共同的细胞 类型. 我们已经证明，大约65%的子宫乳头状浆液性 1 p32-p33区域存在杂合性丢失（洛）。 的 缺失的频率和区域特异性说明了 一种新的肿瘤抑制基因1 p肿瘤抑制因子的发现 参与UPSC肿瘤发生的基因是重要的第一步， 对浆液性癌进行进一步的生物化学和生物学研究。 提出的克隆1 p UPSC肿瘤抑制基因的方法如下 如下：I. 进一步定义1 P上的最小缺失区域， 子宫乳头状浆液性癌。 UPSC肿瘤抑制基因具有 被定位到一个小区域，两侧是标记D1 S190和D1 S447。 我们将建立一个完整的克隆重叠群， 并将设计新的多态性标记。 洛缺失定位研究将 在扩大的肿瘤集合中进行，以进一步 优化最小共有缺失区域。 二. 识别和 表征1 p UPSC肿瘤抑制基因的候选者。 几 方法将用于识别候选基因，并确定是否 他们参与了UPSC的发展。 EST和cDNA作图， 大规模基因组测序，cDNA的直接选择，和外显子 将使用诱捕来识别候选者。 肿瘤将是 使用PCR和单克隆抗体检测候选基因中的突变 链构象变体分析。 拟议的研究将导致 开发UPSC缺失区的转录图谱， UPSC肿瘤抑制基因的发现

The overall goal of this proposal is to clone a tumor suppressor gene involved in the development of the most aggressive form of endometrial cancer, ulterine papillary serous carcinoma (UPSC). Cancer of the endometrium is the most common gynecologic malignancy in the U.S., with an estimated 33,000 new cases each year. Although UPSC accounts for greater than 10 percent of all endometrial cancers, it is responsible for more than half of all endometrial cancer mortality. UPSC and serous carcinoma of the ovary are histologically indistinguishable. They show similar patterns of metastatic spread and it has been suggested that serous cancers of the endometrium and ovary originate from a common cell type. We have shown that approximately 65 percent of uterine papillary serous carcinoma have loss of heterozygosity (LOH) of the 1p32-p33 region. The frequency and regional specificity of deletion speaks to the involvement of a novel tumor suppressor gene. Discovery of the 1p tumor suppressor gene involved in UPSC tumorigenesis is important first step toward further biochemical and biological investigation of serous carcinomas. The methods proposed to clone the 1p UPSC tumor suppressor genes are as follows: I. Further define the minimum region of deletion on 1P in uterine papillary serous carcinomas. The UPSC tumor suppressor gene has been mapped to a small region, flanked by the markers D1S190 and D1S447. We will develop a complete clone contig spanning the region of deletion and new polymorphic markers will be devised. LOH mapping studies will be performed in an expanded collection of tumors in an effort to further refine the minimum consensus region of deletion. II. Identify and characterize candidates for the 1p UPSC tumor suppressor gene. Several methods will be used to identify candidate genes and determine whether they are involved in the development of UPSC. EST and cDNA mapping, large scale genomic sequencing, direct selection of cDNAs, and exon trapping will be used to identify candidates. Tumors will be investigated for mutations in candidate genes using PCR and single strand conformational variant analysis. The proposed studies will lead to the development of a transcript map for the UPSC deletion region and the discovery of a UPSC tumor suppressor gene.