MOLECULAR-GENETIC BASIS OF RENAL CARCINOGENESIS IN THE EKER RAT MODELOF TUBEROUS SCLEROSIS (TSC2)

We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat. The homozygous mutant condition is let hal at around the 13th day of fetal life. In heterozygotes, RCs invari ably develop in the first year of life. Histologically, RCs develop th rough multiple stages from early preneoplastic lesions (i.e., phenotyp ically altered tubules) to adenomas. The wild-type allele mutation has been found even in the earliest preneoplastic lesions, fitting Knudso n's two-hit hypothesis and supporting the hypothesis that Tsc2 is a tu mor suppressor gene. In this study, homozygous deletion of the Ink4 ho mologue on rat chromosome 5q was observed in 14 of 24 (58%) RC-derived cell lines. This may represent involvement of a second tumor suppress or gene, contributing to tumor progression. Considering previous resul ts of studies of homozygous deletion of the Ifn alpha gene in five of 24 cases (21%) and the Ifn beta gene in one of 24 cases (4%), the orde r of the genes may be Ink4--lfn alpha-If beta. Microsatellite instabil ity was not observed in 26 Eker rat tumors. (C) 1995 Wiley-Liss, Inc.