RECESSIVE MUTATIONS IN THE GENESIS OF PROSTATE CANCER

最近的研究已经确定了多种遗传变化中的几种 常见成人肿瘤如结肠、乳腺和 肺癌 影响两类基因的突变，癌基因和 肿瘤抑制基因被认为是最基本的。 而癌基因 是内源性基因的超功能形式， 增殖，肿瘤抑制基因通常起负作用 调节细胞分裂以响应外部生长或分化 信号. 两个抑制等位基因的失活是必要的， 致癌作用;典型的是一个等位基因的隐性突变 另一个野生型等位基因的缺失 两个抑制基因，Rb 染色体13 q14和染色体17 p13上的p53， 研究了 每一种都在普通上皮细胞的相当大一部分中发生突变， 肿瘤以及不常见的肿瘤，如视网膜母细胞瘤、骨或软组织肿瘤， 组织肉瘤、白血病和脑肿瘤，以及野生型- Rb或p53基因能够抑制人的肿瘤表型， 携带适当突变的内源等位基因的肿瘤细胞。 这些 结果强烈表明，这些基因的突变在 多种癌症的起源 尽管它对健康有重大影响， 前列腺癌是男性最常见的癌症， 在基因层面上理解。 据推测，与其他 肿瘤，肿瘤抑制基因的突变有助于肿瘤的发生， 前列腺癌，虽然身份，突变频率和 这些基因的功能作用对于每种癌症类型可能不同。 这 假设将在三个目标中进行测试。 首先，突变和/或等位基因 将研究Rb、4p 53和其他潜在抑制基因座的丢失 在大量冷冻和存档的前列腺肿瘤中， 免疫组织化学和分子遗传学分析。 显著 这些改变与主要临床病理学指标的相关性， 因为肿瘤分期将使我们了解这些肿瘤的特定致癌作用， 基因. 第二，将探索肿瘤抑制的细胞机制 在模型系统中，包括Rb和p53活性的比较 以及它们在抑制肿瘤发生表型中可能的协同作用。 第三，染色体区域经常受到等位基因丢失的影响， 前列腺癌将通过互补的结构和功能 直接证据的方法，他们拥有新的抑制基因座 参与前列腺肿瘤的发生。 这些研究将提供一个分子 遗传框架，以了解发展和进展 前列腺癌，并可能导致新的诊断或治疗方法 前列腺癌的治疗

Recent studies have defined several of the multiple genetic changes underlying the genesis of common adult neoplasms such as colon, breast, and lung carcinoma. Mutations affecting two classes of genes, oncogenes and tumor suppressor genes, are considered most fundamental. Whereas oncogenes are hyperfunctional forms of endogenous genes that promote cellular proliferation, tumor suppressor genes normally function to negatively regulate cell division in response to external growth or differentiation signals. Inactivation of both suppressor alleles is necessary for an oncogenic effect; typically a recessive mutation of one allele is followed by the loss of the other wild-type allele. Two suppressor genes, Rb on chromosome 13q14 and p53 on chromosome 17p13, have been most intensely studied. Each is mutated in a substantial fraction of common epithelial neoplasms as well as unusual tumors such as retinoblastoma, bone or soft- tissue sarcomas, leukemias, and brain tumors, and exogenous copies of wild- type Rb or p53 genes are able to suppress the neoplastic phenotype of human tumor cells bearing the appropriate mutated endogenous alleles. These results strongly suggest that mutations of these genes are significant in the genesis of many types of cancer. Despite its major health impact as the most common cancer in men, prostate carcinoma is relatively poorly understood at the genetic level. It is hypothesized that, as with other neoplasms, mutations of tumor suppressor genes contribute to the genesis of prostate carcinoma, although the identities, mutational frequencies and functional roles of such genes may differ for each cancer type. This hypothesis will be tested in three Aims. First, mutations and/or allelic losses of Rb,4p53 and other potential suppressor loci will be investigated in a large series of frozen and archival prostate tumors using immunohistochemistry and molecular genetic analyses. Significant correlation of such alterations with major clinicopathological indices such as tumor stage will give insight into specific oncogenic roles for these genes. Second, cellular mechanisms of tumor suppression will be explored in a model system, including a comparison of the activities of Rb and p53 and their possible synergy in suppressing the tumorigenic phenotype. Third, chromosomal regions that are frequently affected by allelic loss in prostate cancer will be examined by complementary structural and functional approaches for direct evidence that they harbor novel suppressor loci involved in prostatic oncogenesis. These studies will provide a molecular genetic framework for understanding the development and progression of prostate cancer, and may lead to novel diagnostic or therapeutic approaches to prostate cancer management.