PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

前列腺癌已成为最常被诊断的恶性肿瘤。 在美国的男性中。这种癌症表现出多样化的 从长期休眠到快速休眠的临床行为谱 生长和转移表型。前列腺所经历的步骤 上皮细胞向恶性转化的过程尚不清楚。我们 建议使用以下方法检查前列腺癌的发展情况 包括选择性紫外线辐射在内的新技术 分步(SURF)和DNA指纹图谱 在懒惰的形式之间的遗传差异 疾病和更具侵袭性的肿瘤表型。在……里面 初步实验，我们已经鉴定出P53肿瘤 几种前列腺癌中作为突变靶点的抑癌基因位点 癌症标本并证明了DNA的适用性 指纹图谱在前列腺癌DNA变异检测中的应用 与构成DNA的模式相比。我们还提供了证据 SURF后再进行聚合酶链式反应是合适的 前列腺肿瘤细胞组织学亚群的特异性突变 在档案固定组织切片中。 这项建议旨在通过以下方式进一步发展研究 (1)确定p53基因突变的频率和性质 并比较这些遗传损伤的地形图 (基因型)对某银行前列腺癌细胞表型的影响 在400个组织学分级明确的前列腺切除标本中， 病理分期和DNA倍体；(2)分析鉴定 应用寡核苷酸DNA技术研究前列腺癌的体细胞变化 先天性巨结肠患者正常和肿瘤DNA指纹图谱分析 前列腺癌；(3)基于DNA指纹分析的线索， 前列腺癌相关新基因座特征的研究 确定受突变影响的关键基因；以及(4) 检测不同突变形式的P53，它们已经被 被发现常发生在前列腺癌中，潜在的 在前列腺上皮细胞的背景下，功能获得 文化。 这些相互关联的研究结合在一起，应该会带来新的 对人类前列腺癌发病机制的洞察。

Prostate cancer has become the most frequently diagnosed malignancy of men in the United States. This cancer exhibits a diverse spectrum of clinical behaviors from prolonged dormancy to rapid growth and metastatic phenotypes. The steps through which prostate epithelial cells progress to malignancy remain to be defined. We propose to examine the development of prostate cancer by using novel technologies including selective ultraviolet radiation fractionation (SURF) and DNA fingerprinting which should identify some of the genetic differences between the indolent form of the disease and more aggressive phenotypes of the tumor. In preliminary experiments, we have identified the p53 tumor suppressor gene locus as a target for mutation in several prostate cancer specimens and demonstrated the applicability of DNA fingerprinting in detecting variations in the prostate tumor DNA compared to the constitutive DNA pattern. We also present evidence that SURF followed by PCR is appropriate for the analysis of specific mutations in histologic subsets of prostatic tumor cells in archival fixed tissue sections. This proposal is designed to further develop the research through (1) determination of the frequency and nature of p53 gene mutations and comparison of the topography of these genetic lesions (genotype) to the phenotype of the prostate tumor cells from a bank of 400 prostatectomy specimens well-defined by histologic grade, pathologic stage and DNA ploidy; (2) analysis and identification of somatic changes in prostate cancers by oligonucleotide-based DNA fingerprinting of normal and tumor DNAs of individuals with prostate cancer; (3) based on DNA fingerprinting leads, characterization of new prostate cancer associated gene loci for identification of critical genes affected by the mutation; and (4) examination of different mutant forms of p53, which have been identified to occur commonly in prostate cancers, for potential gain of function, in the context of prostatic epithelial cell cultures. These interconnected studies, in combination, should lead to new insights into the pathogenesis of human prostatic cancer.