An Alternative Route for Multistep Tumorigenesis in a Novel Case of Hereditary Renal Cell Cancer and a t(2;3)(q35;q21) Chromosome Translocation

Abstract

Through allele-segregation and loss-of-heterozygosity analyses, we demonstrated loss of the translocation-derivative chromosome 3 in five independent renal cell tumors of the clear-cell type, obtained from three members of a family in which a constitutional t(2;3)(q35;q21) was encountered. In addition, analysis of the von Hippel-Lindau gene, VHL, revealed distinct insertion, deletion, and substitution mutations in four of the five tumors tested. On the basis of these results, we conclude that, in this familial case, an alternative route for renal cell carcinoma development is implied. In contrast to the first hit in the generally accepted two-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harboring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.

Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation

“…In two living brothers of this family who were diagnosed with renal cell cancers, a t(2;3)(q33;q21) constitutional translocation was found, but it is probable, because of the clinical features of the other five RCC cases that developed in close relatives, that the relatives were also carriers of this chromosomal abnormality. Another family segregating t(2;3)(q35;q21) translocations with multiple cases of RCC was reported by investigators in the Netherlands Bodmer et al 1998;Geurts van Kessel et al 1999). Based on the cytogenetic findings, the Netherland translocations appeared to be similar to our familial translocation.…”

“…As yet, only one member of this family developed bilateral renal cell cancer. More recently, a constitutional translocation t(2;3)(q35;q21) was reported in several Dutch family members over three generations, including four patients with renal cell cancers Bodmer et al 1998;Geurts van Kessel et al 1999). Interestingly, at the same time, we identified a family in Poland transmitting a similar constitutional translocation t(2;3)(q33;q21) (Zajaczek et al 1999).…”

“…Through studies of somatic cell hybrids, Bodmer et al (1998) showed that marker D3S1303 was centromeric to the 3q breakpoint in the Dutch family, and D3S1290 mapped telomeric to it. We physically mapped the 3q break in our familial t(2;3) translocation to the region q13-21.…”

The DIRC1 gene at chromosome 2q33 spans a familial RCC-associated t(2;3)(q33;q21) chromosome translocation

“…Two living brothers presented with early-onset clear cell renal cancer; kidney cancer was also noted in two earlier generations. A Dutch family with a similar constitutional translocation, t(2,3)(q35;q21), had four family members in three generations with RCCs Bodmer et al 1998).…”

“…The gene was proposed as a tumor suppressor gene and experimental support for the proposal continues to accumulate (Ishii et al 2001;Dumon et al 2001). At the same time, a number of investigators suggested that chromosomal translocations can contribute to kidney cancer initiation or progression, in the sporadic or familial setting, through facilitation of tumor-specific loss of derivative chromosomes carrying large portions of the short arm of chromosome 3 (Gnarra et al 1994;Bodmer et al 1998;Eleveld et al 2001), the locus of several proposed renal cancer tumor suppressor genes, including the VHL gene.…”