PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

前列腺癌已成为最常见的恶性肿瘤 在美国的男人。 这种癌症表现出多种多样的 从长期休眠到快速休眠的临床行为谱 生长和转移表型。 前列腺切除的步骤 上皮细胞发展为恶性肿瘤仍有待确定。 我们 建议通过使用 包括选择性紫外线辐射在内的新技术 分级分离（SURF）和DNA指纹图谱， 懒惰型和懒惰型之间的遗传差异 疾病和肿瘤的更具侵袭性的表型。 在 初步实验，我们已经确定了p53肿瘤 抑制基因位点作为几种前列腺突变靶点 癌症标本，并证明了DNA的适用性， 指纹图谱在检测前列腺肿瘤DNA变异中的应用 与组成型DNA模式相比。 我们还提供了证据 SURF后接PCR适合于分析 前列腺肿瘤细胞组织学亚群中的特异性突变 在存档的固定组织切片中。 该提案旨在通过以下方式进一步发展研究： (1)p53基因突变频率和性质的测定 并将这些遗传性病变的形貌进行比较 将来自库的前列腺肿瘤细胞的表型（基因型）与来自库的前列腺肿瘤细胞的表型进行比较。 在400例组织学分级明确的前列腺切除标本中， 病理分期及DNA倍体分析;（2）分析鉴定 前列腺癌的体细胞变化的研究 正常和肿瘤DNA的指纹分析 前列腺癌;（3）基于DNA指纹线索， 新的前列腺癌相关基因位点的表征 识别受突变影响的关键基因;以及（4） 检查不同的突变形式的p53，这已经被 在前列腺癌中常见， 在前列腺上皮细胞的背景下， cultures. 这些相互关联的研究，结合起来，应该会导致新的 了解人类前列腺癌的发病机制。

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.