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. 1993 Feb 15;90(4):1416–1419. doi: 10.1073/pnas.90.4.1416

Homozygous somatic Wt1 point mutations in sporadic unilateral Wilms tumor.

M J Coppes 1, G J Liefers 1, P Paul 1, H Yeger 1, B R Williams 1
PMCID: PMC45884  PMID: 8381965

Abstract

Wilms tumor may be caused by loss of function of genes at different loci. A Wilms tumor suppressor gene, WT1, at chromosome 11 band p13, has recently been cloned and characterized. WT1 has been implicated in the development of Wilms tumor by virtue of mutations in patients with genitourinary anomalies and susceptibility to Wilms tumor. Homozygous intragenic mutations have been reported in Wilms tumors, but usually not in sporadic unilateral Wilms tumors, which constitute the majority of Wilms tumor cases. Using the single-strand conformational polymorphism assay, we have identified three sporadic unilateral Wilms tumors with homozygous point mutations: one with a de novo germ-line nonsense point mutation within WT1 exon 8, and two carrying a somatic mutation within WT1 exon 10. In all three cases loss of the wild-type allele was demonstrated by tumor loss of heterozygosity. This report provides an example of two somatic mutations in the same tumor expected to inactivate WT1 function.

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Selected References

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

  1. Baird P. N., Santos A., Groves N., Jadresic L., Cowell J. K. Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. Hum Mol Genet. 1992 Aug;1(5):301–305. doi: 10.1093/hmg/1.5.301. [DOI] [PubMed] [Google Scholar]
  2. Bird A. The essentials of DNA methylation. Cell. 1992 Jul 10;70(1):5–8. doi: 10.1016/0092-8674(92)90526-i. [DOI] [PubMed] [Google Scholar]
  3. Bonetta L., Kuehn S. E., Huang A., Law D. J., Kalikin L. M., Koi M., Reeve A. E., Brownstein B. H., Yeger H., Williams B. R. Wilms tumor locus on 11p13 defined by multiple CpG island-associated transcripts. Science. 1990 Nov 16;250(4983):994–997. doi: 10.1126/science.2173146. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. Coppes M. J., Bonetta L., Huang A., Hoban P., Chilton-MacNeill S., Campbell C. E., Weksberg R., Yeger H., Reeve A. E., Williams B. R. Loss of heterozygosity mapping in Wilms tumor indicates the involvement of three distinct regions and a limited role for nondisjunction or mitotic recombination. Genes Chromosomes Cancer. 1992 Nov;5(4):326–334. doi: 10.1002/gcc.2870050408. [DOI] [PubMed] [Google Scholar]
  7. Coppes M. J., Liefers G. J., Higuchi M., Zinn A. B., Balfe J. W., Williams B. R. Inherited WT1 mutation in Denys-Drash syndrome. Cancer Res. 1992 Nov 1;52(21):6125–6128. [PubMed] [Google Scholar]
  8. 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]
  9. Davis L. M., Zabel B., Senger G., Lüdecke H. J., Metzroth B., Call K., Housman D., Claussen U., Horsthemke B., Shows T. B. A tumor chromosome rearrangement further defines the 11p13 Wilms tumor locus. Genomics. 1991 Jul;10(3):588–592. doi: 10.1016/0888-7543(91)90440-p. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Henry I., Grandjouan S., Couillin P., Barichard F., Huerre-Jeanpierre C., Glaser T., Philip T., Lenoir G., Chaussain J. L., Junien C. Tumor-specific loss of 11p15.5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma. Proc Natl Acad Sci U S A. 1989 May;86(9):3247–3251. doi: 10.1073/pnas.86.9.3247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature. 1987 Sep 17;329(6136):219–222. doi: 10.1038/329219a0. [DOI] [PubMed] [Google Scholar]
  14. Hogg A., Onadim Z., Baird P. N., Cowell J. K. Detection of heterozygous mutations in the RB1 gene in retinoblastoma patients using single-strand conformation polymorphism analysis and polymerase chain reaction sequencing. Oncogene. 1992 Jul;7(7):1445–1451. [PubMed] [Google Scholar]
  15. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Knudson A. G., Jr, Strong L. C. Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst. 1972 Feb;48(2):313–324. [PubMed] [Google Scholar]
  19. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  20. Lewis W. H., Yeger H., Bonetta L., Chan H. S., Kang J., Junien C., Cowell J., Jones C., Dafoe L. A. Homozygous deletion of a DNA marker from chromosome 11p13 in sporadic Wilms tumor. Genomics. 1988 Jul;3(1):25–31. doi: 10.1016/0888-7543(88)90154-1. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Mannens M., Slater R. M., Heyting C., Bliek J., de Kraker J., Coad N., de Pagter-Holthuizen P., Pearson P. L. Molecular nature of genetic changes resulting in loss of heterozygosity of chromosome 11 in Wilms' tumours. Hum Genet. 1988 Dec;81(1):41–48. doi: 10.1007/BF00283727. [DOI] [PubMed] [Google Scholar]
  23. 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]
  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. Rauscher F. J., 3rd, Morris J. F., Tournay O. E., Cook D. M., Curran T. Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. Science. 1990 Nov 30;250(4985):1259–1262. doi: 10.1126/science.2244209. [DOI] [PubMed] [Google Scholar]
  28. Reeve A. E., Sih S. A., Raizis A. M., Feinberg A. P. Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells. Mol Cell Biol. 1989 Apr;9(4):1799–1803. doi: 10.1128/mcb.9.4.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Royer-Pokora B., Ragg S., Heckl-Ostreicher B., Held M., Loos U., Call K., Glaser T., Housman D., Saunders G., Zabel B. Direct pulsed field gel electrophoresis of Wilms' tumors shows that DNA deletions in 11p13 are rare. Genes Chromosomes Cancer. 1991 Mar;3(2):89–100. doi: 10.1002/gcc.2870030203. [DOI] [PubMed] [Google Scholar]
  30. Ton C. C., Huff V., Call K. M., Cohn S., Strong L. C., Housman D. E., Saunders G. F. Smallest region of overlap in Wilms tumor deletions uniquely implicates an 11p13 zinc finger gene as the disease locus. Genomics. 1991 May;10(1):293–297. doi: 10.1016/0888-7543(91)90516-h. [DOI] [PubMed] [Google Scholar]
  31. Wadey R. B., Pal N., Buckle B., Yeomans E., Pritchard J., Cowell J. K. Loss of heterozygosity in Wilms' tumour involves two distinct regions of chromosome 11. Oncogene. 1990 Jun;5(6):901–907. [PubMed] [Google Scholar]
  32. Yeger H., Cullinane C., Flenniken A., Chilton-MacNeil S., Campbell C., Huang A., Bonetta L., Coppes M. J., Thorner P., Williams B. R. Coordinate expression of Wilms' tumor genes correlates with Wilms' tumor phenotypes. Cell Growth Differ. 1992 Dec;3(12):855–864. [PubMed] [Google Scholar]

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