Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Oct;85(8):1226–1230. doi: 10.1054/bjoc.2001.2072

Analysis of the TSC1and TSC2genes in sporadic renal cell carcinomas

L Parry 1, J H Maynard 1, A Patel 1, S C Clifford 2, C Morrissey 2, E R Maher 2, J P Cheadle 1, J R Sampson 1
PMCID: PMC2375153  PMID: 11710839

Abstract

The genetic events involved in the aetiology of non-clear-cell renal cell carcinoma (RCC) and a proportion of clear cell RCC remain to be defined. Germline mutations of the TSC1and TSC2genes cause tuberous sclerosis (TSC), a multi-system hamartoma syndrome that is also associated with RCC. We assessed 17 sporadic clear cell RCCs with a previously identified VHLmutation, 15 clear-cell RCCs without an identified VHLmutation and 15 non-clear-cell RCCs for loss of heterozygosity (LOH) at chromosomes 9q34 and 16p13.3, the chromosomal locations of TSC1and TSC2. LOH was detected in 4/9, 1/11 and 3/13 cases informative at both loci. SSCP analysis of the whole coding region of the retained allele did not reveal any cases with a detectable intragenic second somatic mutation. Furthermore, RT-PCR analysis of TSC1and TSC2on total RNA from 8 clear-cell RCC cell lines confirmed expression of both TSC genes. These data indicate that biallelic inactivation of TSC1or TSC2is not frequent in sporadic RCC and suggests that the molecular mechanisms of renal carcinogenesis in TSC are likely to be distinct. © 2001 Cancer Research Campaignhttp://www.bjcancer.com  http://www.bjcancer.com

Keywords: TSC1, TSC2, sporadic renal cell carcinoma

Full Text

The Full Text of this article is available as a PDF (73.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Al-Saleem T., Wessner L. L., Scheithauer B. W., Patterson K., Roach E. S., Dreyer S. J., Fujikawa K., Bjornsson J., Bernstein J., Henske E. P. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer. 1998 Nov 15;83(10):2208–2216. [PubMed] [Google Scholar]
  2. Bissig H., Richter J., Desper R., Meier V., Schraml P., Schäffer A. A., Sauter G., Mihatsch M. J., Moch H. Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am J Pathol. 1999 Jul;155(1):267–274. doi: 10.1016/S0002-9440(10)65120-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bjornsson J., Short M. P., Kwiatkowski D. J., Henske E. P. Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol. 1996 Oct;149(4):1201–1208. [PMC free article] [PubMed] [Google Scholar]
  4. Cho M., Konishi N., Kitahori Y., Hiasa Y., Nakagawa Y., Uemura H., Hirao Y., Oosterwijk E. Detection of DNA amplification in human renal cell carcinoma cell lines using restriction landmark genomic scanning. Cell Mol Biol (Noisy-le-grand) 1998 Sep;44(6):913–918. [PubMed] [Google Scholar]
  5. Cho M., Konishi N., Yamamoto K., Inui T., Kitahori Y., Nakagawa Y., Uemura H., Hirao Y., Hiasa Y. Genomic aberrations in renal cell carcinomas detected by restriction landmark genomic scanning. Eur J Cancer. 1998 Dec;34(13):2112–2118. doi: 10.1016/s0959-8049(98)00261-5. [DOI] [PubMed] [Google Scholar]
  6. Clifford S. C., Prowse A. H., Affara N. A., Buys C. H., Maher E. R. Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer. 1998 Jul;22(3):200–209. doi: 10.1002/(sici)1098-2264(199807)22:3<200::aid-gcc5>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  7. Clifford S. C., Walsh S., Hewson K., Green E. K., Brinke A., Green P. M., Gianelli F., Eng C., Maher E. R. Genomic organization and chromosomal localization of the human CUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development. Genes Chromosomes Cancer. 1999 Sep;26(1):20–28. [PubMed] [Google Scholar]
  8. European Chromosome 16 Tuberous Sclerosis Consortium Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993 Dec 31;75(7):1305–1315. doi: 10.1016/0092-8674(93)90618-z. [DOI] [PubMed] [Google Scholar]
  9. Foster K., Prowse A., van den Berg A., Fleming S., Hulsbeek M. M., Crossey P. A., Richards F. M., Cairns P., Affara N. A., Ferguson-Smith M. A. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. 1994 Dec;3(12):2169–2173. doi: 10.1093/hmg/3.12.2169. [DOI] [PubMed] [Google Scholar]
  10. Gnarra J. R., Tory K., Weng Y., Schmidt L., Wei M. H., Li H., Latif F., Liu S., Chen F., Duh F. M. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994 May;7(1):85–90. doi: 10.1038/ng0594-85. [DOI] [PubMed] [Google Scholar]
  11. Henske E. P., Thorner P., Patterson K., Zhuang Z., Bernstein J. Renal cell carcinoma in children with diffuse cystic hyperplasia of the kidneys. Pediatr Dev Pathol. 1999 May-Jun;2(3):270–274. doi: 10.1007/s100249900123. [DOI] [PubMed] [Google Scholar]
  12. Herman J. G., Latif F., Weng Y., Lerman M. I., Zbar B., Liu S., Samid D., Duan D. S., Gnarra J. R., Linehan W. M. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700–9704. doi: 10.1073/pnas.91.21.9700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jones A. C., Daniells C. E., Snell R. G., Tachataki M., Idziaszczyk S. A., Krawczak M., Sampson J. R., Cheadle J. P. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet. 1997 Nov;6(12):2155–2161. doi: 10.1093/hmg/6.12.2155. [DOI] [PubMed] [Google Scholar]
  14. Kobayashi T., Hirayama Y., Kobayashi E., Kubo Y., Hino O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet. 1995 Jan;9(1):70–74. doi: 10.1038/ng0195-70. [DOI] [PubMed] [Google Scholar]
  15. Kobayashi T., Minowa O., Kuno J., Mitani H., Hino O., Noda T. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res. 1999 Mar 15;59(6):1206–1211. [PubMed] [Google Scholar]
  16. Latif F., Tory K., Gnarra J., Yao M., Duh F. M., Orcutt M. L., Stackhouse T., Kuzmin I., Modi W., Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–1320. doi: 10.1126/science.8493574. [DOI] [PubMed] [Google Scholar]
  17. Onda H., Lueck A., Marks P. W., Warren H. B., Kwiatkowski D. J. Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest. 1999 Sep;104(6):687–695. doi: 10.1172/JCI7319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pea M., Bonetti F., Martignoni G., Henske E. P., Manfrin E., Colato C., Bernstein J. Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol. 1998 Feb;22(2):180–187. doi: 10.1097/00000478-199802000-00005. [DOI] [PubMed] [Google Scholar]
  19. Prowse A. H., Webster A. R., Richards F. M., Richard S., Olschwang S., Resche F., Affara N. A., Maher E. R. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet. 1997 Apr;60(4):765–771. [PMC free article] [PubMed] [Google Scholar]
  20. Radford D. M., Fair K. L., Phillips N. J., Ritter J. H., Steinbrueck T., Holt M. S., Donis-Keller H. Allelotyping of ductal carcinoma in situ of the breast: deletion of loci on 8p, 13q, 16q, 17p and 17q. Cancer Res. 1995 Aug 1;55(15):3399–3405. [PubMed] [Google Scholar]
  21. Robertson F. M., Cendron M., Klauber G. T., Harris B. H. Renal cell carcinoma in association with tuberous sclerosis in children. J Pediatr Surg. 1996 May;31(5):729–730. doi: 10.1016/s0022-3468(96)90689-2. [DOI] [PubMed] [Google Scholar]
  22. Sampson J. R., Patel A., Mee A. D. Multifocal renal cell carcinoma in sibs from a chromosome 9 linked (TSC1) tuberous sclerosis family. J Med Genet. 1995 Nov;32(11):848–850. doi: 10.1136/jmg.32.11.848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Satake N., Kobayashi T., Kobayashi E., Izumi K., Hino O. Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (Tsc1) and analysis of its mutations in rat renal carcinomas. Cancer Res. 1999 Feb 15;59(4):849–855. [PubMed] [Google Scholar]
  24. Schmidt L., Duh F. M., Chen F., Kishida T., Glenn G., Choyke P., Scherer S. W., Zhuang Z., Lubensky I., Dean M. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997 May;16(1):68–73. doi: 10.1038/ng0597-68. [DOI] [PubMed] [Google Scholar]
  25. Seymour A. B., Hruban R. H., Redston M., Caldas C., Powell S. M., Kinzler K. W., Yeo C. J., Kern S. E. Allelotype of pancreatic adenocarcinoma. Cancer Res. 1994 May 15;54(10):2761–2764. [PubMed] [Google Scholar]
  26. Shuin T., Kondo K., Torigoe S., Kishida T., Kubota Y., Hosaka M., Nagashima Y., Kitamura H., Latif F., Zbar B. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res. 1994 Jun 1;54(11):2852–2855. [PubMed] [Google Scholar]
  27. Thrash-Bingham C. A., Greenberg R. E., Howard S., Bruzel A., Bremer M., Goll A., Salazar H., Freed J. J., Tartof K. D. Comprehensive allelotyping of human renal cell carcinomas using microsatellite DNA probes. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2854–2858. doi: 10.1073/pnas.92.7.2854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Urakami S., Tokuzen R., Tsuda H., Igawa M., Hino O. Somatic mutation of the tuberous sclerosis (Tsc2) tumor suppressor gene in chemically induced rat renal carcinoma cell. J Urol. 1997 Jul;158(1):275–278. doi: 10.1097/00005392-199707000-00085. [DOI] [PubMed] [Google Scholar]
  29. Verdorfer I., Culig Z., Hobisch A., Bartsch G., Hittmair A., Duba H. C., Erdel M. Characterisation of a collecting duct carcinoma by cytogenetic analysis and comparative genomic hybridisation. Int J Oncol. 1998 Sep;13(3):461–464. doi: 10.3892/ijo.13.3.461. [DOI] [PubMed] [Google Scholar]
  30. Vogelstein B., Fearon E. R., Kern S. E., Hamilton S. R., Preisinger A. C., Nakamura Y., White R. Allelotype of colorectal carcinomas. Science. 1989 Apr 14;244(4901):207–211. doi: 10.1126/science.2565047. [DOI] [PubMed] [Google Scholar]
  31. Yeung R. S., Xiao G. H., Everitt J. I., Jin F., Walker C. L. Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat. Mol Carcinog. 1995 Sep;14(1):28–36. doi: 10.1002/mc.2940140107. [DOI] [PubMed] [Google Scholar]
  32. van Slegtenhorst M., de Hoogt R., Hermans C., Nellist M., Janssen B., Verhoef S., Lindhout D., van den Ouweland A., Halley D., Young J. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805–808. doi: 10.1126/science.277.5327.805. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES