A constitutional balanced t(3;8)(p14;q24.1) translocation results in disruption of the TRC8 gene and predisposition to clear cell renal cell carcinoma

Studying the molecular basis of familial renal cell carcinoma (RCC) has allowed identification of novel RCC genes involved in the pathogenesis of both inherited and sporadic RCC. We describe a constitutional balanced t(3;8)(p14;q24.1) translocation found in a brother and sister with bilateral clear cell RCC (CC-RCC) diagnosed in their forties. Consistent with a prior report, we demonstrated by RT-PCR of RNA from lymphoblastoid cells fusion mRNAs derived from the fragile histidine triad (FHIT) at 3p14 and TRC8 at 8q24.1 in both affected siblings. Cytogenetic analysis of a CC-RCC tumor from the affected sister from short-term tumor cell culture showed both diploid and pseudotetraploid populations containing the translocation and normal appearing chromosomes 3 and 8. Fluorescent in situ hybridization using bacterial artificial chromosomes containing sequences from the FHIT and TRC8 genes demonstrated normal FHIT signals and TRC8 signals on nontranslocated chromosomes in the constitutional blood sample, but the TRC8 signal was absent in a subset of diploid and pseudotetraploid cells from the tumor. The tumor also contained a heterozygous VHL frameshift somatic mutation. These results confirm that balanced translocations disrupting the TRC8 and FHIT genes result in an increased genetic susceptibility for bilateral CC-RCC. The presence of diploid and tetraploid tumor cells with and without TRC8 deletions on the nontranslocated chromosome suggest that loss of the remaining normal allele of TRC8 may contribute to tumor development at later stages.