Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat.
Somatic events leading to the inactivation of tumor suppressor genes often involve chromosomal alterations that can be detected as loss of heterozygosity (LOH). In the Eker rat, spontaneous tumors of the kidney, uterus, and spleen develop as a result of a germline mutation of the tuberous sclerosis 2 (Tsc2) gene. We examined the pattern and frequency of LOH at the predisposing locus in 77 primary tumors and cell lines to gain an understanding of the role of Tsc2 allelic loss in the pathogenesis of Eker-derived tumors. Although most renal and uterine tumors (primary and cell lines) displayed LOH, splenic hemangiosarcomas did not. Although the presence of normal tissue may account for some of this difference, the possibility exists that an alternative mechanism, such as subtle mutation or gene dosage effects, may be involved during splenic tumorigenesis. Northern analysis confirmed that LOH resulted in loss of the wild-type transcripts for the Tsc2 gene. Thus, the inactivation of both alleles plays an important role in renal and uterine tumor development, in keeping with Knudson's two-hit hypothesis. In addition, renal tumors that retained the wild-type allele also did not express the normal transcript, suggesting that the remaining Tsc2 alleles had acquired subtle mutations resulting in loss of gene function.
Yeung
R S
RS
Division of Medical Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Xiao
G H
GH
Everitt
J I
JI
Jin
F
F
Walker
C L
CL
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002460:Cell Line; D002872:Chromosome Deletion; D017931:DNA Primers; D005091:Exons; D005260:Female; D016147:Genes, Tumor Suppressor; D006394:Hemangiosarcoma / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics*; D007889:Leiomyoma / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D051381:Rats; D011922:Rats, Mutant Strains; D013160:Splenic Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic; D014402:Tuberous Sclerosis / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics*
D017931:DNA Primers