CLONING A UTERINE SEROUS CARCINOMA TUMOR SUPPRESSOR GENE

这项提议的总体目标是克隆一种肿瘤抑制基因 参与最具侵袭性的子宫内膜的形成 恶性乳头状浆液性癌(UPSC)。巨蟹座 子宫内膜是美国最常见的妇科恶性肿瘤， 据估计，每年有3.3万例新病例。尽管UPSC占 超过10%的子宫内膜癌是由它引起的 占所有子宫内膜癌死亡率的一半以上。UPSC和Serous 卵巢癌在组织学上难以区分。他们展示了 类似的转移扩散模式，并已提出 浆液性子宫内膜癌和卵巢癌起源于一个共同的细胞 打字。 我们已经证明，大约65%的子宫乳头状浆液性病变 癌组织具有1p32-p33区域的杂合性缺失(LOH)。这个 缺失的频率和区域特异性说明了这一点 一种新的肿瘤抑制基因。1P抑癌基因的发现 参与UPSC肿瘤发生的基因是迈向 进一步的浆液性癌的生化和生物学研究。 建议克隆1p UPSC抑癌基因的方法如下： 以下：I.进一步定义1P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 被绘制到一个小区域，两侧是D1S190和D1S447。 我们将开发一个跨越缺失区域的完整克隆重叠群 并将设计出新的多态标记。陆恭蕙地图研究将会 在扩大的肿瘤集合中进行，以努力进一步 细化删除的最小共识区域。二、识别和 鉴定1p UPSC肿瘤抑制基因的候选基因。几个 方法将被用来识别候选基因并确定 他们参与了UPSC的发展。EST和cDNA作图， 大规模基因组测序、cDNA和外显子的直接选择 陷阱将被用来识别候选人。肿瘤将会是 用聚合酶链式反应和单链构象分析研究候选基因的突变 链构象变异分析。拟议的研究将导致 为UPSC缺失区和UPSC缺失区域的转录图谱的开发 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.