Allelic Loss at the Tuberous Sclerosis (Tsc2) Gene Locus in Spontaneous Uterine Leiomyosarcomas and Pituitary Adenomas in the Eker Rat Model

Hereditary renal carcinomas (RCs) develop in virtually all Eker rats by the age of one year. Investigation of extra‐renal primary tumors co‐occurring in Eker rats late in life (at 2 years) additionally revealed enhanced development of hemangiosarcomas of the spleen, uterine leiomyosarcomas and pituitary adenomas, although the demonstrated predilection for these extra‐renal tumors was not as complete as with RCs. We identified the germline mutated tuberous sclerosis (Tsc2) gene as the predisposing Eker gene and revealed the tumor suppressor nature of Tsc2 gene function in renal carcinogenesis. In the present study, we examined allelic loss at the Tsc2 gene locus in uterine leiomyosarcomas and pituitary adenomas developing in hybrid F1 rats carrying the Eker mutation as well as in pituitary adenomas from non‐carrier rats. We detected loss of heterozygosity in 4 of 11 uterine leiomyosarcomas (36%) and 11 of 31 pituitary adenomas (35%) from Eker rats but in none of 9 pituitary adenomas from non‐carrier rats (P<0.05), suggesting that inactivation of the Tsc2 gene is also a critical event in the pathogenesis of these extra‐renal tumors. Our present data indicate that there might be different pathways for tumorigenesis of pituitary adenomas between Eker and non‐carrier rats.

[1]  Y. Kubo,et al.  Early detection of Knudson's two-hits in preneoplastic renal cells of the Eker rat model by the laser microdissection procedure. , 1995, Cancer research.

[2]  A. Knudson,et al.  Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Kobayashi,et al.  The predisposing gene of the Eker rat inherited cancer syndrome is tightly linked to the tuberous sclerosis (TSC2) gene. , 1994, Biochemical and biophysical research communications.

[4]  Y. Kubo,et al.  A novel cancer predisposition syndrome in the Eker rat model. , 1994, Cancer letters.

[5]  K. Post,et al.  Loss of heterozygosity at the retinoblastoma locus in human pituitary tumors , 1994, Cancer.

[6]  Y. Kubo,et al.  Allelic loss at the predisposing gene locus in spontaneous and chemically induced renal cell carcinomas in the Eker rat. , 1994, Cancer research.

[7]  J. Brooks,et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma , 1994, Nature Genetics.

[8]  A. Bradley,et al.  Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. , 1994, Oncogene.

[9]  R. Thakker,et al.  Molecular genetic studies of sporadic pituitary tumors. , 1994, The Journal of clinical endocrinology and metabolism.

[10]  S. Thomas,et al.  Identification and characterization of the tuberous sclerosis gene on chromosome 16 , 1993, Cell.

[11]  O. Hino,et al.  A Novel Renal Cell Carcinoma Susceptibility Gene Maps on Chromosome 10 in the Eker Rat , 1993, Japanese journal of cancer research : Gann.

[12]  A. Knudson,et al.  Susceptibility to renal carcinoma in the Eker rat involves a tumor suppressor gene on chromosome 10. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[13]  T. Goldsworthy,et al.  Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome. , 1992, The Journal of urology.

[14]  F. Mitelman,et al.  Chromosome analysis of 96 uterine leiomyomas. , 1991, Cancer genetics and cytogenetics.

[15]  Yasushi Kikuchi.  Lectin‐ and Immunohistochemical Studies on Acquired Cystic Kidney and Associated Renal Cell Carcinoma , 1989, Acta pathologica japonica.

[16]  O. Hino,et al.  Relationship between serum and histochemical markers for hepatitis B virus and rate of viral integration in hepatocellular carcinomas in Japan , 1985, International journal of cancer.

[17]  J. Mossige,et al.  A Dominant Gene for Renal Adenomas in the Rat , 1961, Nature.

[18]  Y. Kubo,et al.  A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer , 1995, Nature Genetics.

[19]  A. Knudson,et al.  Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.