MOLECULAR GENETICS OF PROSTATE CANCER

为了调查与启动有关的遗传事件 和前列腺癌的进展，来自泌尿外科肿瘤学的科学家 美国国立卫生研究院分部(UOB)和病理实验室(LOP)已经做出了 使用了一系列以 异种来源高纯度前列腺癌细胞的获取 组织。允许这种采购的新型显微解剖技术 都是在LOP中开发的；最新的这种技术涉及激光 细胞的捕获大大提高了解剖的速度和纯度。 染色体缺失通常发现在基因的附近 保护细胞免受癌变。使用从99制备的DNA 通过显微解剖肿瘤，大华大学的科学家们分析了45个遗传标记 跨越了许多染色体区域，以前 与前列腺癌的发生有关。最高的删除率是 在人类8号染色体上观察到，总的缺失率为86%。 大约80%的癌症共享一个共同的缺失区域 在8号染色体(8p21)内。这个地区最近还重叠了一个地区 被确认为家族性乳腺癌的基因座。 人类前列腺癌被认为是通过癌前病变进展的 进展期称为前列腺上皮内瘤变(PIN) 转化为浸润性癌症。在8号染色体上通常缺失的区域 癌症，63%的PIN病变中也发现了缺失。这个结果 提示8p21的异常可能与早期阶段有关 前列腺癌的发展。 该地区的物理地图目前正在UOB中构建， 大华大学和LOP团队已经开始分析候选基因 居住在这个地区。 LOP的科学家发现，显微解剖的前列腺样本也 产生了高质量的RNA，这使得他们和大华大学的团队能够 分析正常组织和肿瘤组织中基因表达的差异。在……里面 除了直接寻找各种基因在特定环境中的表达 细胞群体、包含表达基因序列的文库 作为多学科癌症基因组解剖学的一部分构建 项目(CGAP)。构建了20个前列腺库，覆盖了 生物学的光谱从正常到癌前到局部和 转移性癌。这些文库在基因组上进行了测序 华盛顿大学测序中心，发现表现出高 已知和迄今未发现的基因的质量表示。 来自大规模文库测序的数据允许识别和 比较肿瘤进展不同阶段表达的基因。 所产生的信息被用来指导选择 映射到8p21的候选基因。 最后，为了扩大可供检查的资源 前列腺癌在活细胞中的作用，细胞系是通过 来自大华大学和外科分部的科学家。这些线是生成的 从9名接受根治性前列腺切除术的患者的组织中提取 4例晚期前列腺癌患者在 美国国家情报局。这些品系将为未来的体外生长研究奠定基础。

In order to investigate the genetic events associated with the initiation and progression of prostate cancer, scientists from the Urologic Oncology Branch (UOB) and the Laboratory of Pathology (LOP) at the NCI have made use of a number of innovative methodologies centered around the procurement of highly purified prostatic cancer cells from heterogeneous tissue. Novel microdissection techniques which allow such procurement were developed in the LOP; the most recent such technique involving laser capture of cells greatly increased the speed and purity of dissection. Chromosomal deletions are often found in the vicinity of genes that protect cells from becoming cancerous. Using DNA prepared from 99 microdissected tumors, scientists in the UOB analyzed 45 genetic markers spanning a number of chromosomal regions that had been previously implicated in prostate carcinogenesis. The highest rate of deletion was observed on human chromosome 8, where the overall rate of loss was 86%. Approximately 80% of the cancers shared a common region of deletion within chromosome 8 (8p21). This region also overlaps a region recently identified as a locus for familial breast cancer. Human prostate cancer is thought to progress through a pre-malignant phase called prostatic intraepithelial neoplasia (PIN) prior to evolving into invasive cancer. In the region of chromosome 8 commonly deleted in cancer, deletions were also found in 63% of PIN lesions. This result suggests that abnormalities on 8p21 may be associated with early stages of prostate cancer development. A physical map of the region is currently being constructed in the UOB, and the UOB and LOP teams have begun analyzing candidate genes which reside in this area. Scientists in the LOP found that microdissected prostate samples also yielded good quality RNA, which has allowed them and the UOB team to analyze differences in gene expression in normal vs. tumor tissue. In addition to looking directly for expression of various genes in specific cell populations, libraries containing expressed genetic sequences were constructed as part of the multidisciplinary Cancer Genome Anatomy Project (CGAP). Twenty prostate libraries were constructed covering a spectrum of biology from normal to pre-malignant to localized and metastatic cancer. These libraries were sequenced at the Genome Sequencing Center at Washington University and found to exhibit high quality representation of both known and heretofore undiscovered genes. Data from large scale library sequencing allows for identification and comparison of genes expressed at distinct stages of tumor progression. The information generated is being used to guide the selection of candidate genes which map to 8p21. Finally, in order to expand upon the available resources for examination of prostate cancer in living cells, cell lines were established by scientists from the UOB and the Surgery Branch. The lines were generated from tissue from nine patients who underwent radical prostatectomy and four patients with advanced prostate cancer who underwent biopsy at the NCI. These lines will allow for future in vitro growth studies.