MOLECULAR-GENETIC ANALYSIS OF 3P14 GENOMIC STABILITY

描述(改编自《调查者摘要》)：遗传性 肾癌3；8易位是相当大的 癌症遗传学家的兴趣和这个实验室的长期目标。 该病是一种典型的常染色体遗传性癌症。 显性遗传，多灶性早发性肾癌和少见 通常情况下，是甲状腺癌。调查人员是第一个克隆 3p14易位断裂点。他们随后的调查发现 不同肿瘤细胞系中涉及某一区域的纯合子缺失 T(3；8)断裂点附近约150 kb的端粒。这一地区 与基因组中最易诱发的脆性部位FRA3B重合。 涉及FRA3B的缺失是否完全由基因组引起 不稳定，或者是生物选择的，是一个重要的问题，给定 3P丢失在多种恶性疾病中出现的频率较高。而当 Ohta等人。发现了一个跨越3；8断裂点的3p14基因FHIT，其 作为肿瘤抑制因子的角色一直受到严重质疑。调查人员 已经发现3；8易位导致融合转录本 一个新基因TRC8和FHIT之间的关系。推测TRC8基因是一种 与果蝇Patted部分相似的膜受体 其同源基因与遗传性基底细胞癌有关 综合症。关于不同的3p14缺失区， 调查人员已经获得了其他非FHIT成绩单和 已经确定了一种细胞系CC19，该细胞系正在进行自发缺失 FRA3B表现出肿瘤发生的差异。该系统提供了一种理想的 模型来研究FHIT和其他假定基因的致癌作用。 因此，调查人员提出了两个主要调查领域：1) TRC8的进一步特征包括突变分析 肾癌和甲状腺癌.亚细胞抗体的研制 正常和重排产物的定位.转基因实验 对TRC8、TRC8-FHIT和FHIT-TRC8产品进行功能特性分析。2)至 阐明3p14缺失在癌症中的作用，他们将研究 缺失和不缺失影响FHIT的CC19亚克隆的致瘤性 外显子。如果缺失与肿瘤发生之间一致的相关性 可以获得变异，他们将进行转基因实验 FHIT确认此活动。如果建议使用非FHIT编码区 具有肿瘤抑制活性的它们将被进一步表征。

DESCRIPTION (Adapted from the Investigator's Abstract): The hereditary renal carcinoma 3;8 translocation has been the source of considerable interest among cancer geneticists and a long-term goal of this laboratory. The pattern of disease is one of classic hereditary cancer with autosomal dominant inheritance, multifocal early onset renal cancer and less frequently, thyroid cancer. The investigators were the first to clone the 3p14 translocation breakpoint. Their subsequent investigations identified homozygous deletions in various carcinoma cell lines involving a region approximately 150 kb telomeric to the t(3;8) breakpoint. This region coincides with FRA3B, the most inducible fragile site in the genome. Whether or not the deletions involving FRA3B result solely from genomic instability, or are biologically selected, is an important question, given the high frequency of 3p loss in a variety of malignant diseases. While Ohta et al. identified a 3p14 gene, FHIT, spanning the 3;8 breakpoint, its role as a tumor suppressor has been seriously questioned. The investigators have discovered that the 3;8 translocation results in a fusion transcript between a novel gene, TRC8, and FHIT. The TRC8 gene is suggested to be a membrane receptor with partial similarity to Drosophila patched, the human homologue of which is responsible for the hereditary basal cell carcinoma syndrome. With regard to the distinct 3p14 deletion region, the investigators have obtained evidence for additional non-FHIT transcripts and have identified a cell line, CC19, with ongoing spontaneous deletions in FRA3B which exhibit tumorigenic differences. This system provides an ideal model to investigate the tumorigenic role of FHIT and other putative genes. The investigators propose, therefore, two main areas of investigation: 1) The further characterization of TRC8 including a mutational analysis of renal and thyroid carcinomas; development of antibodies for the subcellular localization of normal and rearranged products; transfection experiments to functionally characterize the TRC8, TRC8-FHIT and FHIT-TRC8 products. 2) To clarify the role of 3p14 deletions in cancer, they will examine the tumorigenesis of CC19 subclones with and without deletions affecting FHIT exons. If consistent correlations between deletions and tumorigenic variation can be obtained, they will perform transfection experiments with FHIT to confirm this activity. If non-FHIT coding regions are suggested to have tumor suppressor activity they will be further characterized.