Terminal deletion of chromosome 3p sequences in nonpapillary renal cell carcinomas: a breakpoint cluster between loci D3S1285 and D3S1603.

Deletion of chromosome 3p13-pter sequences is a specific genetic change in nonpapillary renal cell carcinomas (RCC). The VHL gene, a putative tumor suppressor gene, has already been cloned from the 3p25-26 chromosomal region. Conflicting cytogenetic and RFLP studies, however, suggest multiple interstitial deletions and additional tumor suppressor genes at chromosome 3p. To investigate the loss of DNA sequences on chromosome 3p in nonpapillary RCCs, we analyzed 41 paired normal and tumor DNAs obtained from short-term cultures of pure tumor cells with 12 polymorphic microsatellite markers covering the 3p11.2-p25 region. Deletion mapping provided evidence for terminal deletion with the most distal breakpoint between D3S1300 and D3S1285 loci, which is the site of breakpoint in familial 3;8 translocation predisposing to nonpapillary RCC. All breakpoints, including those occurring in familial translocation 3;6, were clustered in a more than 20-cM-large region between loci D3S1285 and D3S1603. Interestingly, 7 of the 28 cases with 3p deletion showed a recurrent breakpoint between D3S1603 and D3S1595, which cover about 1 cM genetic distance. The results suggest that a tumor suppressor gene, in addition to the VHL gene, might be localized somewhere on chromosome 3p distal to the familial 3;8 translocation, or it might be at the breakpoint cluster. Alternatively, the breakpoint serves as a mechanism to lose distal DNA sequences.