MOLECULAR-GENETIC ANALYSIS OF 3P14 GENOMIC STABILITY

描述（改编自研究者摘要）：遗传性 肾癌3;8易位已成为相当大的来源， 癌症遗传学家的兴趣和这个实验室的长期目标。 其发病方式为典型的常染色体遗传性癌症 显性遗传，多灶性早发性肾癌， 经常是甲状腺癌。 研究人员是第一个克隆 3 p14易位断裂点。 他们随后的调查发现 在涉及一个区域的各种癌细胞系中的纯合缺失 在端粒的t（3;8）断点处约150 kb。 这一地区 与基因组中最易诱导的脆性位点FRA 3B一致。 涉及FRA 3B的缺失是否仅由基因组 不稳定性，或生物选择，是一个重要的问题，鉴于 多种恶性疾病中3 p丢失的高频率。 而 Ohta等鉴定了3 p14基因FHIT，其跨越3;8断裂点， 作为肿瘤抑制剂的作用受到严重质疑。 调查人员 已经发现3;8易位导致融合转录物 新基因TRC 8和FHIT之间的联系 TRC 8基因被认为是 膜受体与部分相似果蝇补丁，人类 其同源物是遗传性基底细胞癌的原因 综合征 对于不同的3 p14缺失区， 调查人员已经获得了额外的非FHIT成绩单的证据， 已经确定了一个细胞系，CC 19，与正在进行的自发缺失， FRA 3B，其表现出致瘤性差异。 该系统提供了一个理想的 模型研究FHIT和其他推定基因的致瘤作用。 因此，调查人员提出了两个主要调查领域：1） TRC 8的进一步表征包括以下突变分析： 肾癌和甲状腺癌;亚细胞癌抗体的产生 正常和重排产物的定位;转染实验， 功能上表征TRC 8、TRC 8-FHIT和FHIT-TRC 8产物。 2)到 为了阐明3 p14缺失在癌症中的作用，他们将研究 FHIT基因缺失和未缺失CC 19亚克隆的肿瘤发生 外显子 如果缺失和肿瘤发生之间存在一致的相关性， 可以获得变异，他们将进行转染实验， FHIT确认该活动。 如果建议非FHIT编码区 具有肿瘤抑制活性，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.