The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.
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.
Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA. gemmill@loki.uchsc.edu
R M
RM
Gemmill
J D
JD
West
F
F
Boldog
N
N
Tanaka
L J
LJ
Robinson
D I
DI
Smith
F
F
Li
H A
HA
Drabkin
D017766:Acid Anhydride Hydrolases; D000595:Amino Acid Sequence; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D002898:Chromosomes, Human, Pair 8; D017931:DNA Primers; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface; D017386:Sequence Homology, Amino Acid; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D017931:DNA Primers; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D000099170:Bis(5'-adenosyl)triphosphatase; C114025:RNF139 protein, human