MARKERS OF PROGRESSION AND METASTASES

前列腺癌是美国男性最常见的癌症。 发生率 一直在急剧增加，年龄别死亡率 也在增加，虽然速度更慢。 日益扩大的差距 发病率和死亡率可能反映了成功的早期发现， 可能致命的癌症 但是，组织学癌症的患病率 低恶性潜能是如此之高（在50岁以上的男性中约为4- 0 旧），现在发现的一些癌症可能没有什么临床意义， 重要性 表征恶性潜能的当前技术 在临床上，在前列腺被切除之前，是不够的。 活检 样本不能充分代表患者的癌症。 活检通常低估了分级，分期研究通常 低估了癌症的严重程度，所以倾向于治疗每一个发现的癌症 可能致命 这些都是少数公认的客观指标， 除了等级，能够预测预后-无论是局部复发率， 生长或转移的可能性-具有足够的准确性， 适当的管理。 该项目的目的是制定更好的方法来评估 前列腺癌带来的威胁 我们的首要目标是发展得更好 针吸活检的策略， 可以获得准确反映生物学潜能的 治疗已经开始。 我们的第二个目标是确定新的标记物， 进展和转移倾向，并制定标准的有效 验证关于建立预后的有希望的标志物的方案 特点和结果。 我们对候选标记物的评估和开发 涉及一种系统方法，并部分基于一种范式， 认为生长和转移潜力可能在 进展的早期阶段。 标准统计方法可能是 在检测标记物和转移性肿瘤之间的复杂关系方面效率低下， 潜力 这些方法可以通过计算机密集型 建模技术 我们以前曾报道过一种新的预后 指标，凋亡指数（A.I），并将继续发展这一标志物 因为它的临床效用。 我们还将扩大免疫组织化学 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， 独自一人。 我们将扩大我们对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， 检测一小部分细胞中的突变 我们特别 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TGF-β受体2的突变， 在转移性病变中的高频率检测，与匹配的 原发性肿瘤 最后，我们将使用代表性差异分析 (RDA)发现转移瘤中同源缺失基因的技术比较 原发肿瘤，可作为转移的新标志物， 在原发肿瘤中的能力。

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.