Cloning and characterization of a 6p cervical cancer tsg

描述：（由申请人提供）浸润性宫颈癌（ICC）是 世界上第五大最常见的恶性肿瘤，占40万例， 年已经确定了一些独立的风险因素， 人乳头瘤病毒（HPV）感染是最一致的。八十到九十 %的ICC为病毒阳性。然而，HPV感染本身并不是 宫颈癌的发病率是多少？ 到70%的妇女被感染，但恶性肿瘤的发展在不到8 百分之因此，遗传变化必须在肿瘤发展中发挥作用。在 初步的实验表明，50%的肿瘤测试已经失去了 人类6号染色体短臂的全部或部分， 对ICC的发展至关重要，它位于那里。我们最新的数据显示 我们将该区域缩小到400 kb，几乎完全测序， 桑格中心 该提案的目的是确定6pZ 3中导致ICC的基因。 在候选区域内发现的成绩单将从 通过实验或基于计算机的方法进行测序。在后一 我们还将对小鼠基因组进行基于同源性的分析， 正在为此项目生成的序列。我们已经找到了2到4个 基因在可用的序列。所有候选基因将被表征为 他们的表达方式。宫颈上皮中表达的基因将被 在肿瘤中筛选6p缺失的突变。用于突变筛查 我们将获得每个基因结构的数据，包括其全长， 序列和内含子/外显子连接。我们将筛选出被删除的肿瘤 通过DHPLC和PCR产物的直接测序检测突变的RNA或DNA。一旦 肿瘤抑制基因被确定，我们广泛的宫颈肿瘤库将 进行突变筛查，结果与临床和病理相关 因素此外，旨在确定该基因的 功能，如在细胞周期中的调节，与其他细胞的相互作用 周期控制基因等，将被启动。基因的鉴定 在宫颈癌的发生中起重要作用， 诊断和预后标志物，以降低发病率和死亡率， 这个癌症

DESCRIPTION: (provided by applicant) Invasive cervical cancer (ICC) is the fifth most common malignancy in the world, accounting for 400,000 cases per year. A number of independent risk factors have been identified of which infection by human papillomavirus (HPV) is the most consistent. Eighty to 90 percent of ICCs are virus-positive. However, HPV infection alone is not sufficient for the development of cervical cancer since in some populations up to 70 percent of women are infected yet the malignancy develops in less than 8 percent. Therefore, genetic changes must play a role in tumor development. In preliminary experiments we show that 50 percent of all tumors tested have lost all or part of the short arm of human chromosome 6 suggesting that a gene, important for the development of ICC, is located there. Our latest data allowed us to narrow down the region to 400 kb that is almost completely sequenced by the Sanger Center. The aim of this proposal is to identify the gene in 6pZ3 that causes ICC. Transcripts found within the candidate region will be identified from the sequence by either experimental or computer-based methods. In the latter category we will also perform homology-based analysis with the mouse genomic sequence that is being generated for this project. We already found 2 to 4 genes in the available sequence. All candidate genes will be characterized for their pattern of expression. Genes expressed in cervical epithelium will be screened for mutations in the tumors with 6p deletions. For mutation screening we will obtain data on each gene's structure, including its full-length sequence and the intron/exon junctions. We will screen either deleted tumor RNAs or DNAs for mutations by DHPLC and direct sequencing of PCR products. Once the tumor suppressor gene is identified, our extensive cervical tumor bank will be screened for mutations and the results correlated to clinical and pathologic factors. In addition, experiments aimed at the determination of the gene's function such as its regulation during cell cycle, interaction with other cell cycle controlled genes etc., will be initiated. Identification of a gene important in cervical carcinogenesis will allow the development of better diagnostic and prognostic markers to reduce the morbidity and mortality from this cancer.