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. 1994 Apr 26;91(9):3554–3558. doi: 10.1073/pnas.91.9.3554

Fine structure analysis of the WT1 gene in sporadic Wilms tumors.

R Varanasi 1, N Bardeesy 1, M Ghahremani 1, M J Petruzzi 1, N Nowak 1, M A Adam 1, P Grundy 1, T B Shows 1, J Pelletier 1
PMCID: PMC43618  PMID: 8170946

Abstract

Molecular genetic studies indicate that the etiology of Wilms tumor (WT) is complex, involving at least three loci. Germ-line mutations in the tumor suppressor gene, WT1, have been documented in children with WTs and urogenital developmental anomalies. Sporadic tumors constitute the majority (> 90%) of WT cases and previous molecular analyses of the WT1 gene have focused only on the DNA-binding domain. Using the single-strand conformational polymorphism (SSCP) assay, we analyzed the structural integrity of the entire WT1 gene in 98 sporadic WTs. By PCR-SSCP we find that mutations in the WT1 gene are rare, occurring in only six tumors analyzed. In one sample, two independent intragenic mutations inactivated both WT1 alleles, providing a singular example of two different somatic alterations restricted to the WT1 gene. This case is consistent with the existence of only one tumor suppressor gene at 11p13 involved in the pathogenesis of WTs. Our data, together with the previously ascertained occurrence of large deletions/insertions in WT1, define the frequency at which the WT1 gene is altered in sporadic tumors.

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Selected References

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  1. Beckwith J. B., Kiviat N. B., Bonadio J. F. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms' tumor. Pediatr Pathol. 1990;10(1-2):1–36. doi: 10.3109/15513819009067094. [DOI] [PubMed] [Google Scholar]
  2. Brown K. W., Watson J. E., Poirier V., Mott M. G., Berry P. J., Maitland N. J. Inactivation of the remaining allele of the WT1 gene in a Wilms' tumour from a WAGR patient. Oncogene. 1992 Apr;7(4):763–768. [PubMed] [Google Scholar]
  3. Bruening W., Bardeesy N., Silverman B. L., Cohn R. A., Machin G. A., Aronson A. J., Housman D., Pelletier J. Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development. Nat Genet. 1992 May;1(2):144–148. doi: 10.1038/ng0592-144. [DOI] [PubMed] [Google Scholar]
  4. Call K. M., Glaser T., Ito C. Y., Buckler A. J., Pelletier J., Haber D. A., Rose E. A., Kral A., Yeger H., Lewis W. H. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9;60(3):509–520. doi: 10.1016/0092-8674(90)90601-a. [DOI] [PubMed] [Google Scholar]
  5. Coppes M. J., Liefers G. J., Paul P., Yeger H., Williams B. R. Homozygous somatic Wt1 point mutations in sporadic unilateral Wilms tumor. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1416–1419. doi: 10.1073/pnas.90.4.1416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cowell J. K., Wadey R. B., Haber D. A., Call K. M., Housman D. E., Pritchard J. Structural rearrangements of the WT1 gene in Wilms' tumour cells. Oncogene. 1991 Apr;6(4):595–599. [PubMed] [Google Scholar]
  7. Gerald W. L., Gramling T. S., Sens D. A., Garvin A. J. Expression of the 11p13 Wilms' tumor gene, WT1, correlates with histologic category of Wilms' tumor. Am J Pathol. 1992 May;140(5):1031–1037. [PMC free article] [PubMed] [Google Scholar]
  8. Gessler M., Poustka A., Cavenee W., Neve R. L., Orkin S. H., Bruns G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. doi: 10.1038/343774a0. [DOI] [PubMed] [Google Scholar]
  9. Haber D. A., Buckler A. J., Glaser T., Call K. M., Pelletier J., Sohn R. L., Douglass E. C., Housman D. E. An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell. 1990 Jun 29;61(7):1257–1269. doi: 10.1016/0092-8674(90)90690-g. [DOI] [PubMed] [Google Scholar]
  10. Harris C. C., Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med. 1993 Oct 28;329(18):1318–1327. doi: 10.1056/NEJM199310283291807. [DOI] [PubMed] [Google Scholar]
  11. Hofmann W., Royer H. D., Drechsler M., Schneider S., Royer-Pokora B. Characterization of the transcriptional regulatory region of the human WT1 gene. Oncogene. 1993 Nov;8(11):3123–3132. [PubMed] [Google Scholar]
  12. Huang A., Campbell C. E., Bonetta L., McAndrews-Hill M. S., Chilton-MacNeill S., Coppes M. J., Law D. J., Feinberg A. P., Yeger H., Williams B. R. Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor. Science. 1990 Nov 16;250(4983):991–994. doi: 10.1126/science.2173145. [DOI] [PubMed] [Google Scholar]
  13. Huff V., Miwa H., Haber D. A., Call K. M., Housman D., Strong L. C., Saunders G. F. Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT. Am J Hum Genet. 1991 May;48(5):997–1003. [PMC free article] [PubMed] [Google Scholar]
  14. Ichikawa T., Ichikawa Y., Dong J., Hawkins A. L., Griffin C. A., Isaacs W. B., Oshimura M., Barrett J. C., Isaacs J. T. Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11. Cancer Res. 1992 Jun 15;52(12):3486–3490. [PubMed] [Google Scholar]
  15. Kikuchi H., Akasaka Y., Nagai T., Umezawa A., Iri H., Kato S., Hata J. Genomic changes in the WT-gene (WT1) in Wilms' tumors and their correlation with histology. Am J Pathol. 1992 Apr;140(4):781–786. [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Kreidberg J. A., Sariola H., Loring J. M., Maeda M., Pelletier J., Housman D., Jaenisch R. WT-1 is required for early kidney development. Cell. 1993 Aug 27;74(4):679–691. doi: 10.1016/0092-8674(93)90515-r. [DOI] [PubMed] [Google Scholar]
  18. Little M. H., Dunn R., Byrne J. A., Seawright A., Smith P. J., Pritchard-Jones K., van Heyningen V., Hastie N. D. Equivalent expression of paternally and maternally inherited WT1 alleles in normal fetal tissue and Wilms' tumours. Oncogene. 1992 Apr;7(4):635–641. [PubMed] [Google Scholar]
  19. Little M. H., Prosser J., Condie A., Smith P. J., Van Heyningen V., Hastie N. D. Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4791–4795. doi: 10.1073/pnas.89.11.4791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. MILLER R. W., FRAUMENI J. F., Jr, MANNING M. D. ASSOCIATION OF WILMS'S TUMOR WITH ANIRIDIA, HEMIHYPERTROPHY AND OTHER CONGENITAL MALFORMATIONS. N Engl J Med. 1964 Apr 30;270:922–927. doi: 10.1056/NEJM196404302701802. [DOI] [PubMed] [Google Scholar]
  21. Matsunaga E. Genetics of Wilms' tumor. Hum Genet. 1981;57(3):231–246. doi: 10.1007/BF00278936. [DOI] [PubMed] [Google Scholar]
  22. Orita M., Suzuki Y., Sekiya T., Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. doi: 10.1016/0888-7543(89)90129-8. [DOI] [PubMed] [Google Scholar]
  23. Park S., Bernard A., Bove K. E., Sens D. A., Hazen-Martin D. J., Garvin A. J., Haber D. A. Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour. Nat Genet. 1993 Dec;5(4):363–367. doi: 10.1038/ng1293-363. [DOI] [PubMed] [Google Scholar]
  24. Pavletich N. P., Pabo C. O. Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A. Science. 1991 May 10;252(5007):809–817. doi: 10.1126/science.2028256. [DOI] [PubMed] [Google Scholar]
  25. Pelletier J., Bruening W., Kashtan C. E., Mauer S. M., Manivel J. C., Striegel J. E., Houghton D. C., Junien C., Habib R., Fouser L. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991 Oct 18;67(2):437–447. doi: 10.1016/0092-8674(91)90194-4. [DOI] [PubMed] [Google Scholar]
  26. Pelletier J., Bruening W., Li F. P., Haber D. A., Glaser T., Housman D. E. WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature. 1991 Oct 3;353(6343):431–434. doi: 10.1038/353431a0. [DOI] [PubMed] [Google Scholar]
  27. Pelletier J., Schalling M., Buckler A. J., Rogers A., Haber D. A., Housman D. Expression of the Wilms' tumor gene WT1 in the murine urogenital system. Genes Dev. 1991 Aug;5(8):1345–1356. doi: 10.1101/gad.5.8.1345. [DOI] [PubMed] [Google Scholar]
  28. Pritchard-Jones K., Fleming S., Davidson D., Bickmore W., Porteous D., Gosden C., Bard J., Buckler A., Pelletier J., Housman D. The candidate Wilms' tumour gene is involved in genitourinary development. Nature. 1990 Jul 12;346(6280):194–197. doi: 10.1038/346194a0. [DOI] [PubMed] [Google Scholar]
  29. Riccardi V. M., Sujansky E., Smith A. C., Francke U. Chromosomal imbalance in the Aniridia-Wilms' tumor association: 11p interstitial deletion. Pediatrics. 1978 Apr;61(4):604–610. [PubMed] [Google Scholar]
  30. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sheffield V. C., Beck J. S., Kwitek A. E., Sandstrom D. W., Stone E. M. The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics. 1993 May;16(2):325–332. doi: 10.1006/geno.1993.1193. [DOI] [PubMed] [Google Scholar]
  32. Shipman R., Schraml P., Colombi M., Raefle G., Ludwig C. U. Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma. Hum Genet. 1993 Jun;91(5):455–458. doi: 10.1007/BF00217771. [DOI] [PubMed] [Google Scholar]
  33. Tadokoro K., Fujii H., Ohshima A., Kakizawa Y., Shimizu K., Sakai A., Sumiyoshi K., Inoue T., Hayashi Y., Yamada M. Intragenic homozygous deletion of the WT1 gene in Wilms' tumor. Oncogene. 1992 Jun;7(6):1215–1221. [PubMed] [Google Scholar]

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