POSITIONAL CLONING OF THE HEREDITARY RENAL-CARCINOMA 3-8 CHROMOSOME-TRANSLOCATION BREAKPOINT

The chromosome (p14.2;q24.1) translocation t(3;8)has been associated w ith hereditary renal cancer in one family. Based on cytogenetic analys es and loss-of-heterozygosity experiments, the 3p14 region has been in dependently implicated as harboring a tumor suppressor gene critical t o kidney and lung cancer development. The 3p14.2 region also contains FRA3B, the most sensitive fragile site induced by aphidicolin. A chrom osome 3 probe, R7K145, derived from a radiation-reduced hybrid was pos itioned between the t(3;8) breakpoint and an aphidicolin-induced 3p14 breakpoint. A yeast artificial chromosome (YAC) contig containing R7K1 45 was developed that crossed the aphidicolin-induced breakpoint on it s telomeric side. A subsequent chromosome walk identified a YAC that c rossed the 3;8 translocation breakpoint. A lambda sublibrary allowed i solation of clones spanning the rearrangement. Unique and evolutionari ly conserved DNA sequences were used to screen a kidney cDNA library. We have identified a gene, referred to as HRCA1 (hereditary renal canc er associated 1), that maps immediately adjacent to the breakpoint. On the basis of its chromosomal position, HRCA1 may be a candidate tumor suppressor gene.