MOLECULAR-GENETIC ANALYSIS OF 3P14 GENOMIC STABILITY

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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.