MARKERS OF PROGRESSION AND METASTASES

前列腺癌是美国男性最常见的癌症。发病率 一直在急剧增加，与年龄相关的死亡率是 也在增加，尽管速度较慢。两国之间日益扩大的差距 发病率和死亡率可能反映了成功的早期检测 可能致命的癌症。但是，组织学癌症的患病率与 低恶性潜能如此之高(50岁以上男性约为4%-0% 一些现在正在检测的癌症可能没有什么临床意义 重要性。当前表征恶性潜能的技术 在临床上，在切除前列腺之前，是不够的。活组织检查 标本不能充分代表病人的癌症。 活检通常低估了分级，而分期研究通常 低估了程度，所以倾向于治疗每一种被发现的癌症 具有潜在致命性。这些都是少数几个公认的客观指标， 而不是分级，能够预测预后-无论是局部 生长或转移的概率-具有足够的准确性 适当的管理。 这个项目的目的是开发更好的方法来评估 前列腺癌带来的威胁。我们的首要目标是发展得更好 针吸活组织检查的策略，以便癌症的代表性样本 可以得到准确反映以前的生物潜力的 治疗开始了。我们的第二个目标是确定新的标记 进展和转移倾向，并制定标准的有效率 关于建立预后的验证有前景的标志物的协议 特点和结果。我们对候选标记物的评估和发展 涉及系统化方法，并部分基于 认为增长和转移潜力可能会在 进展的早期阶段。标准的统计方法可能是 在检测标志物和转移之间的复杂关系方面效率低下 潜力。这些方法可能会得到计算机密集型的补充 建模技术。我们之前曾报道过一种新的预后 指标，细胞凋亡指数(A.I)，并将继续开发这一标志 因为它的临床用途。我们还将扩大我们的免疫组织化学 研究表明局灶性P53阳性染色结合阳性 Ki-67染色具有显著的预后潜力 只有记号笔。我们将扩大对P53的研究，在我们的第三个目标中， 通过使用一种新的分子生物学方法TA-克隆-SSCP分析， 它在一小部分细胞中检测突变。我们特别是 对与转移能力相关的基因改变感兴趣。我们 将研究例如p53和转化生长因子-β受体2的突变， 与匹配的转移灶相比，在转移灶中可高频检测到 原发肿瘤。最后，我们将使用代表性差异分析 (RDA)技术在转移瘤中发现纯合缺失基因的比较 原发肿瘤，可作为转移的新标记物 原发肿瘤的容量。

Prostate cancer is the most common cancer in American men. The incidence has been increasing dramatically and the age-specific mortality rate is also increasing, though more slowly. The growing disparity between incidence and mortality may reflect the successful early detection of potentially lethal cancers. But, the prevalence of histologic cancers with low malignant potential is so high (about 4-0% in men more than 50 years old) that some cancers now being detected may be of little clinical importance. Current techniques for characterizing malignant potential clinically, before the prostate is removed, are inadequate. The biopsy specimen is not sufficiently representative of the cancer in the patient. A biopsy usually underestimates the grade, and staging studies usually underestimate the extent, so the tendency is to treat every detected cancer as potentially lethal. These are few well-established objective markers, other than grade, able to predict prognosis - either athe rate of local growth or the probability of metastasis - with sufficient accuracy for appropriate management. The purpose of this project is to develop better methods to assess the threat posed by a prostate-cancer. Our first aim is to develop better strategies for needle biopsies so that representative samples of the cancer can be obtained which accurately reflect biological potential before treatment is begun. Our second aim is to identify new markers of progression and metastatic propensity and to develop a standard efficient protocol to validate promising markers with respect to establish prognostic features and outcome. Our assessment and development of candidate markers involve a systematic approach and are based in part on a paradigm which considers that growth and metastatic potential may become uncoupled at early stages of progression. Standard statistical approaches may be inefficient at detecting complex relationships among markers and metastatic potential. These approaches may be complemented by computer intensive modeling techniques. We have previously reported a novel prognostic indicator, apoptotic index (A.I) and will continue to develop this marker for its clinical utility. We will also expand our immunohistochemical studies that indicate focal p53 positive staining combined with positive Ki-67 staining has significant prognostic potential beyond that of either marker alone. We will extent our investigations of p53, in our third aim, by using a novel molecular-biological approach, TA-cloning-SSCP analysis, which detects mutations in a small fraction of cells. We are particularly interested in genetic alterations associated with metastatic capacity. We will investigate mutation in, for example, p53 and TGF-beta receptor 2, detectable at high frequency in metastatic lesions compared to a matched primary tumor. Finally, we will use representational difference analysis (RDA) technology to find genes homozygously deleted in metastases compared to the primary tumor, which could be used as novel markers of metastatic capacity in the primary tumor.