MOLECULAR GENETICS OF PROSTATE CANCER

前列腺癌的分子遗传学

• 批准号: 6123760
• 负责人: William Marston Linehan
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6123760
• 关键词: biopsy; carcinogenesis; cell line; cellular oncology; chromosome deletion; clinical research; dissection; early diagnosis; gene expression; genetic library; genetic mapping; genetic markers; human genetic material tag; human subject; lasers; male; metastasis; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; nucleic acid sequence; prostate neoplasms; prostate surgery

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.

为了研究与启动相关的遗传事件， 和前列腺癌的进展，泌尿肿瘤学的科学家们 分支（大华银行）和病理学实验室（LOP）在NCI已经作出了 使用一些创新的方法，围绕 从异质性前列腺癌细胞中获得高度纯化的前列腺癌细胞 组织.新的显微切割技术，允许这样的采购 在LOP中开发;最新的此类技术涉及激光 细胞的捕获大大提高了解剖的速度和纯度。 染色体缺失通常发生在 保护细胞免于癌变。使用从99个 通过显微解剖肿瘤，大华银行的科学家分析了45个遗传标记， 跨越了许多染色体区域， 与前列腺癌的发生有关删除率最高的是 在人类8号染色体上观察到，总的丢失率为86%。 大约80%的癌症共享一个共同的缺失区域 8号染色体（8 p21）。这一地区也与最近的一个地区重叠 被鉴定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。 前列腺上皮内瘤变（PIN） 转化为侵袭性癌症在8号染色体的区域中， 在63%的PIN病变中也发现了缺失。这一结果 提示8 p21的异常可能与早期阶段有关， 前列腺癌的发展。 大华银行目前正在绘制该地区的物理地图， UOB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，显微切割的前列腺样本也 产生了高质量的RNA，这使他们和大华银行团队能够 分析正常与肿瘤组织中基因表达的差异。在 除了直接寻找不同基因在特定细胞中的表达外， 细胞群，含有表达的遗传序列的文库， 作为多学科癌症基因组解剖学的一部分， 项目（援助最贫穷者协商组）。构建了20个前列腺文库， 从正常到癌前到局部和 转移性癌症这些文库在Genome测序 华盛顿大学测序中心发现， 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进行鉴定和分析。 在肿瘤进展的不同阶段表达的基因的比较。 产生的信息用于指导选择 定位于8 p21的候选基因。 最后，为了扩大现有的审查资源， 前列腺癌的活细胞，细胞系建立， 大华银行和外科分支的科学家们这些线条是由 来自9名接受根治性乳房切除术的患者的组织， 四名晚期前列腺癌患者在 NCI这些细胞系将用于未来的体外生长研究。