PREDISPOSITION TO RENAL-CARCINOMA IN THE EKER RAT IS DETERMINED BY GERM-LINE MUTATION OF THE TUBEROUS-SCLEROSIS-2 (TSC2) GENE

Genetic predisposition to neoplasia often involves tumor suppressor ge nes. One such model of hereditary renal carcinoma was described in the rat by Eker. These tumors share morphologic similarities with human r enal cancer. Linkage analysis localized the inherited mutation to rat chromosome band 10q12. This region is syntenic with human chromosome b and 16p13.3, the site of the tuberous sclerosis 2 (TSC2) gene. A speci fic rearrangement of the rat homologue of TSC2 was found to cosegregat e with carriers of the predisposing mutation. Tumors with or without l oss of heterozygosity expressed only the mutant allele, consistent wit h the two-hit hypothesis. This mutation gave rise to an aberrant trans cript that deletes the 3' end normally containing a region of homology with the catalytic domain of rap1GAP.