Molecular genetic basis of renal carcinogenesis in the Eker rat model of 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 lethal at around the 13th day of fetal life. In heterozygotes, RCs invariably develop in the first year of life. Histologically, RCs develop through multiple stages from early preneoplastic lesions (i.e., phenotypically altered tubules) to adenomas. The wild-type allele mutation has been found even in the earliest preneoplastic lesions, fitting Knudson's two-hit hypothesis and supporting the hypothesis that Tsc2 is a tumor suppressor gene. In this study, homozygous deletion of the Ink4 homologue on rat chromosome 5q was observed in 14 of 24 (58%) RC-derived cell lines. This may represent involvement of a second tumor suppressor gene, contributing to tumor progression. Considering previous results 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 order of the genes may be Ink4-Ifn alpha-Ifn beta. Microsatellite instability was not observed in 26 Eker rat tumors.
Hino
O
O
Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Kobayashi
E
E
Hirayama
Y
Y
Kobayashi
T
T
Kubo
Y
Y
Tsuchiya
H
H
Kikuchi
Y
Y
Mitani
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D005313:Fetal Death; D005804:Genes, Lethal; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011247:Pregnancy; D047428:Protein Kinase Inhibitors; D051381:Rats; D011922:Rats, Mutant Strains; D017386:Sequence Homology, Amino Acid; D014402:Tuberous Sclerosis / Q000235:genetics*; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493969:Cdkn2b protein, rat; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins