THE HEREDITARY RENAL-CELL CARCINOMA 3-8-TRANSLOCATION FUSES FHIT TO APATCHED-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 carcinom a,]Previous studies demonstrated that the 3p14.2 breakpoint interrupts the fragile histidine triad gene (FHIT) in its 5' noncoding region. H owever, evidence that FHIT is causally related to renal or other malig nancies is controversial. We now show that the 8q24.1 breakpoint regio n encodes a 664-aa multiple membrane spanning protein, TRC8, with simi larity to the hereditary basal cell carcinoma/segment polarity gene, p atched. This similarity involves two regions of patched, the putative sterol-sensing domain and the second extracellular loop that participa tes in the binding of sonic hedgehog, In the 3;8 translocation, TRC8 i s fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. In a ser ies of sporadic renal carcinomas, an acquired TRC8 mutation was identi fied. By analogy to patched, TRC8 might function as a signaling recept or and other pathway members, to be defined, are mutation candidates i n malignant diseases involving the kidney and thyroid.