Search

Item does not contain fulltext We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional cloning of the 3q21 chromosomal breakpoint revealed that this breakpoint disrupts a novel gene, DIRC2 (disrupted in renal cancer 2). This gene encodes an evolutionary conserved transmembrane protein and represents a novel member of the MFS superfamily of transporters. To evaluate whether DIRC2 is also targeted in sporadic RCC cases with cytogenetically defined 3q21 breakpoints, fluorescence in situ hybridization analysis was performed on metaphase spreads and/or interphase nuclei of 12 primary sporadic RCC using genomic clones from a 3q21 breakpoint-spanning contig as probes. Three breakpoints were mapped proximal to the familial breakpoint and nine breakpoints were mapped distal to this breakpoint. Two of the latter breakpoints were mapped in the contig within 1 Mb distance from the familial breakpoint. Because these clustered 3q21 breakpoints do not coincide with the familial 3q21 breakpoint, they most likely affect genes distinct from DIRC2.

Two sisters affected with renal cell carcinoma (RCC) is an extremely rare finding, and may indicate a hereditary pattern or the presence of other predisposing factors. We describe here 2 sisters presenting with clear cell renal cell cancer. Examination for von Hippel-Lindau (VHL)-related features and tuberous sclerosis (M. Bourneville) was negative and both had a normal constitutional karyotype. Cytogenetic analysis of the tumor tissue of both patients showed a translocation involving chromosomes 3 and 5, resulting in loss of 3p sequences and gain of part of 5q. The 5q breakpoints were similar, but the breakpoints at 3p appeared to differ. Allelic imbalance analysis supported our observations. Microsatellite analysis revealed that both sisters inherited different chromosome 3 parental alleles. For chromosome 5, 3 different haplotypes could be deduced, but the chromosome 5 alleles overrepresented in the different tumor tissues were from different parental origin. The development of the 2 RCCs in these 2 sisters thus cannot be explained by the inheritance of a mutated VHL gene located at 3p25, nor by the inheritance of other gene defects at chromosomes 3p or 5q. Although the chance that 2 sisters develop sporadic RCC is very low, in the presented case it is probably coincidental or related to another genetic predisposition.