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 chang e in nonpapillary renal cell carcinomas (RCC). The VHL gene, a putativ e tumor suppressor gene, has already been cloned from the 3p25-26 chro mosomal region. Conflicting cytogenetic and RFLP studies, however, sug gest multiple interstitial deletions and additional tumor suppressor g enes at chromosome 3p. To investigate the loss of DNA sequences on chr omosome 3p in nonpapillary RCCs, we analyzed 41 paired normal and tumo r DNAs obtained from short-term cultures of pure tumor cells with 12 p olymorphic microsatellite markers covering the 3p11.2-p25 region, Dele tion mapping provided evidence for terminal deletion with the most dis tal 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 translocat ion 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 deletio n showed a recurrent breakpoint between D3S1603 and D3S1595, which cov er about 1 cM genetic distance. The results suggest that a tumor suppr essor 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.