Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients (original) (raw)

. 1996 Dec;149(6):2089–2094.

Abstract

Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal lesions including cysts and renal cell carcinomas (RCCs). VHL gene deletions have been previously reported in VHL-associated macroscopic RCC. Although histological analysis suggests that microscopic cystic lesions in the VHL patients may represent precursors of the RCC, there is at present no direct molecular evidence of their relationship. To investigate the relationship between cystic lesions and RCC, 26 microdissected archival renal lesions from two VHL disease patients were studied for loss of heterozygosity at the VHL gene locus using polymerase chain reaction single-strand conformation polymorphism analysis. The renal lesions included 2 benign cysts, 5 atypical cysts, 5 microscopic RCCs in situ, 5 cysts lined by a single layer of cells, in which RCCs in situ were developing, and 2 microscopic and 7 macroscopic RCCs. Except for a single benign cyst, 25 of 26 renal lesions showed nonrandom allelic loss of the VHL gene. In either of the 2 patients, the same VHL allele was deleted in all of the lesions tested, indicating loss of the wild-type allele and retention of the inherited, mutated VHL allele. The results suggest that all clear-cell lesions in the VHL kidney represent neoplasms and that the loss of the VHL gene occurs early in their development. Atypical and benign cysts most likely represent the initial phenotype in malignant transformation to the RCC.

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  1. Anglard P., Tory K., Brauch H., Weiss G. H., Latif F., Merino M. J., Lerman M. I., Zbar B., Linehan W. M. Molecular analysis of genetic changes in the origin and development of renal cell carcinoma. Cancer Res. 1991 Feb 15;51(4):1071–1077. [PubMed] [Google Scholar]
  2. Chen F., Kishida T., Yao M., Hustad T., Glavac D., Dean M., Gnarra J. R., Orcutt M. L., Duh F. M., Glenn G. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66–75. doi: 10.1002/humu.1380050109. [DOI] [PubMed] [Google Scholar]
  3. Choyke P. L., Glenn G. M., Walther M. M., Zbar B., Weiss G. H., Alexander R. B., Hayes W. S., Long J. P., Thakore K. N., Linehan W. M. The natural history of renal lesions in von Hippel-Lindau disease: a serial CT study in 28 patients. AJR Am J Roentgenol. 1992 Dec;159(6):1229–1234. doi: 10.2214/ajr.159.6.1442389. [DOI] [PubMed] [Google Scholar]
  4. Fuhrman S. A., Lasky L. C., Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982 Oct;6(7):655–663. doi: 10.1097/00000478-198210000-00007. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Hosoe S., Brauch H., Latif F., Glenn G., Daniel L., Bale S., Choyke P., Gorin M., Oldfield E., Berman A. Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3. Genomics. 1990 Dec;8(4):634–640. doi: 10.1016/0888-7543(90)90249-t. [DOI] [PubMed] [Google Scholar]
  7. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kragel P. J., Walther M. M., Pestaner J. P., Filling-Katz M. R. Simple renal cysts, atypical renal cysts, and renal cell carcinoma in von Hippel-Lindau disease: a lectin and immunohistochemical study in six patients. Mod Pathol. 1991 Mar;4(2):210–214. [PubMed] [Google Scholar]
  9. Lamiell J. M., Salazar F. G., Hsia Y. E. von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 1989 Jan;68(1):1–29. doi: 10.1097/00005792-198901000-00001. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Poston C. D., Jaffe G. S., Lubensky I. A., Solomon D., Zbar B., Linehan W. M., Walther M. M. Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications. J Urol. 1995 Jan;153(1):22–26. doi: 10.1097/00005392-199501000-00009. [DOI] [PubMed] [Google Scholar]
  12. Shinohara N., Nonomura K., Harabayashi T., Togashi M., Nagamori S., Koyanagi T. Nephron sparing surgery for renal cell carcinoma in von Hippel-Lindau disease. J Urol. 1995 Dec;154(6):2016–2019. [PubMed] [Google Scholar]
  13. Solomon D., Schwartz A. Renal pathology in von Hippel-Lindau disease. Hum Pathol. 1988 Sep;19(9):1072–1079. doi: 10.1016/s0046-8177(88)80089-3. [DOI] [PubMed] [Google Scholar]
  14. Tory K., Brauch H., Linehan M., Barba D., Oldfield E., Filling-Katz M., Seizinger B., Nakamura Y., White R., Marshall F. F. Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst. 1989 Jul 19;81(14):1097–1101. doi: 10.1093/jnci/81.14.1097. [DOI] [PubMed] [Google Scholar]
  15. Walther M. M., Choyke P. L., Hayes W., Shawker T. H., Alexander R. B., Linehan W. M. Evaluation of color Doppler intraoperative ultrasound in parenchymal sparing renal surgery. J Urol. 1994 Dec;152(6 Pt 1):1984–1987. doi: 10.1016/s0022-5347(17)32285-1. [DOI] [PubMed] [Google Scholar]
  16. Walther M. M., Choyke P. L., Weiss G., Manolatos C., Long J., Reiter R., Alexander R. B., Linehan W. M. Parenchymal sparing surgery in patients with hereditary renal cell carcinoma. J Urol. 1995 Mar;153(3 Pt 2):913–916. [PubMed] [Google Scholar]
  17. Walther M. M., Lubensky I. A., Venzon D., Zbar B., Linehan W. M. Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol. 1995 Dec;154(6):2010–2015. [PubMed] [Google Scholar]
  18. Zbar B., Brauch H., Talmadge C., Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. 1987 Jun 25-Jul 1Nature. 327(6124):721–724. doi: 10.1038/327721a0. [DOI] [PubMed] [Google Scholar]
  19. Zhuang Z., Bertheau P., Emmert-Buck M. R., Liotta L. A., Gnarra J., Linehan W. M., Lubensky I. A. A microdissection technique for archival DNA analysis of specific cell populations in lesions < 1 mm in size. Am J Pathol. 1995 Mar;146(3):620–625. [PMC free article] [PubMed] [Google Scholar]