8P ALLELIC AND CHROMOSOME 8 INSTABILITY IN HUMAN PROSTATE CANCER

人类前列腺癌中的 8P 等位基因和 8 号染色体不稳定性

• 批准号: 6237679
• 负责人: Jill A. Macoska
• 金额: $ 19.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237679
• 关键词: DNA; chromosomes; cytogenetics; epithelium; gene deletion mutation; histopathology; human genetic material tag; human subject; in situ hybridization; male; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplasm /cancer invasiveness; prognosis; prostate; prostate neoplasms; prostate preneoplastic state; prostate specific antigen; relapse /recurrence

Cytogenetic and molecular biological studies have demonstrated deletion of one or more sequence domains that map to the short arm of chromosome 8 (8p) in tumors from several organ systems, including human prostate tumors. Recent studies in our laboratory utilizing interphase fluorescence in situ hybridization (FISH) analysis of prostate tissue sections with unique sequence and pericentromeric probes demonstrate high (>70%) frequencies of 8p22 sequence losses in prostate tissue, sometimes accompanied by gain or loss of other chromosome 8 sequences. Based upon these observations, we hypothesize that: 1) "simple" allelic loss of 8p sequences (e.g., deletion of specific 8p sequences alone without alterations of chromosome 8 dosage) is an important event in prostate tumorigenesis, but that 2) the process of prostate tumorigenesis may be further promoted by a) concurrent or subsequent changes in the dosage (gain or loss) of other linked chromosome 8 loci, and b) a widespread rather than focal pattern of 8p allelic loss and/or chromosome 8 dosage alterations in the tumor. If this hypothesis is true, we would expect our studies to show that, within tumors with 8p loss that share "identical" clinicopathological characteristics, there exists a subset of tumors with widespread (rather than focal) 8p allelic loss and/or alterations in chromosome 8 dosage that are more likely to recur with worse prognosis after radical prostatectomy. Therefore, the goals of this project are to utilize FISH techniques to determine the frequency and pattern of 8p sequence deletions and chromosome 8 dosage alterations as part of a genetic model of prostate tumorigenesis, and to ascertain which of these factors might serve as indicators of worse prognosis. To accomplish these goals, we have organized the research into three specific aims: SPECIFIC AIM 1: Define and compare the frequency of 8p sequence losses and chromosome 8 dosage alterations in: a) normal and hyperplastic (BPH) prostatic epithelium; b) prostatic intraepithelial neoplasias (PINs); c) malignant lesions from "less advanced" cancers (Gleason score 4-6 and localized disease) and those from "more advanced" cancers (Gleason score 7-9 and invasive disease); SPECIFIC AIM 2: Define the type and pattern of 8p sequence losses or changes in chromosome 8 dosage (widespread or focal) in tissues by enumerating probe signal within discrete microscopic coordinates; SPECIFIC AIM 3: Determine whether the frequency, type, pattern or dosage of 8p sequence losses and chromosome 8 dosage alterations may serve as useful prognostic indicators by determining whether they predict tumor recurrence, using serum PSA and other clinical parameters as indicators of recurrence. The information obtained in pursuit of these goals should be useful towards defining the roles of 8p sequence losses and chromosome 8 dosage in one or more potential neoplastic pathways in the prostate, and in defining the potential prognostic significance of these events.

细胞遗传学和分子生物学研究表明， 一个或多个定位于染色体8短臂的序列结构域 (8p)在包括人类前列腺在内的几种器官系统的肿瘤中， 肿瘤的 我们实验室最近的研究利用相间 前列腺组织的荧光原位杂交（FISH）分析 具有独特序列和近着丝粒探针的切片显示出高的 前列腺组织中8 p22序列丢失的频率>70%，有时 伴随着其他8号染色体序列的增加或丢失。 基于 根据这些观察结果，我们假设：1）8 p的“简单”等位基因丢失 序列（例如，仅缺失特定的8 p序列， 染色体8剂量的改变）是前列腺中的重要事件 肿瘤发生，但2）前列腺肿瘤发生的过程可能是 a）同时或随后改变剂量 (gain或丢失）其他连锁的8号染色体基因座，和B）广泛分布的 而不是8 p等位基因丢失和/或8号染色体剂量的局灶性模式 肿瘤的变化。 如果这个假设是正确的，我们可以预期， 研究表明，在8 p缺失的肿瘤中， 临床病理特征，存在一个肿瘤子集， 广泛的（而不是局部的）8 p等位基因丢失和/或改变， 8号染色体剂量更可能复发，预后更差 在根治性乳房切除术后。 因此，本项目的目标是 利用FISH技术来确定8 p的频率和模式 序列缺失和8号染色体剂量改变， 前列腺肿瘤发生的遗传模型，并确定这些 这些因素可能是预后不良的指标。 完成这些 我们将研究分为三个具体目标： 具体目标1：定义和比较8 p序列丢失的频率 和8号染色体剂量改变：a）正常和增生（BPH） 前列腺上皮; B）前列腺上皮内瘤变（PIN）; C） 来自“较不晚期”癌症的恶性病变（Gleason评分4-6， 局限性疾病）和“更晚期”癌症（Gleason评分 7-9（侵袭性疾病）; 具体目标2：定义8 p序列丢失的类型和模式， 组织中8号染色体剂量的变化（广泛或局灶性）， 在离散的微观坐标内计数探针信号; 具体目标3：确定是否频率，类型，模式或剂量 8 p序列丢失和8号染色体剂量改变可能是 有用的预后指标，通过确定它们是否预测肿瘤 复发，使用血清PSA和其他临床参数作为指标， 复发 为实现这些目标而获得的信息应该是有用的 为了确定8 p序列丢失和8号染色体剂量的作用， 在前列腺的一个或多个潜在的肿瘤途径中， 确定这些事件的潜在预后意义。