The Hereditary Renal Cell Carcinoma 3;8 Translocation Fuses FHIT to a Patched-Related Gene, TRC8

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 16; pp. 9572 - 9577
• Main Authors: Gemmill, Robert M., West, James D., Boldog, Ferenc, Tanaka, Naotake, Robinson, Linda J., Smith, David I., Li, Frederick, Drabkin, Harry A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 04-08-1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Acid Anhydride Hydrolases; Amino Acid Sequence; Amino acids; Base Sequence; Biological Sciences; Cancer; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell lines; Cells; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 8; Complementary DNA; DNA Primers; Exons; Genes; Genetic mutation; Humans; Hybridity; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membranes; Molecular Sequence Data; Mutation; Neoplasm Proteins - genetics; Proteins; Proteins - genetics; Receptors, Cell Surface; Renal cell carcinoma; Sequence Homology, Amino Acid; Translocation, Genetic; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.16.9572

The 3;8 chromosomal translocation, t(3;8)(p14.2;q24.1), was described in a family with classical features of hereditary renal cell carcinoma. Previous studies demonstrated that the 3p14.2 breakpoint interrupts the fragile histidine triad gene (FHIT) in its 5′noncoding region. However, evidence that FHIT is causally related to renal or other malignancies is controversial. We now show that the 8q24.1 breakpoint region encodes a 664-aa multiple membrane spanning protein, TRC8, with similarity to the hereditary basal cell carcinoma/segment polarity gene, patched. This similarity involves two regions of patched, the putative sterol-sensing domain and the second extracellular loop that participates in the binding of sonic hedgehog. In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. In a series of sporadic renal carcinomas, an acquired TRC8 mutation was identified. By analogy to patched, TRC8 might function as a signaling receptor and other pathway members, to be defined, are mutation candidates in malignant diseases involving the kidney and thyroid.