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. 1995 Mar;56(3):608–615.

Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome.

T Frebourg 1, N Barbier 1, Y X Yan 1, J E Garber 1, M Dreyfus 1, J Fraumeni Jr 1, F P Li 1, S H Friend 1
PMCID: PMC1801151  PMID: 7887414

Abstract

Germ-line mutations of the tumor-suppressor gene p53 have been observed in some families with the Li-Fraumeni syndrome (LFS), a familial cancer syndrome in which affected relatives develop a diverse set of early-onset malignancies including breast carcinoma, sarcomas, and brain tumors. The analysis of the p53 gene in LFS families has been limited, in most studies to date, to the region between exon 5 and exon 9. In order to determine the frequency and distribution of germ-line p53 mutations in LFS, we sequenced the 10 coding exons of the p53 gene in lymphocytes and fibroblast cell lines derived from 15 families with the syndrome. Germ-line mutations were observed in eight families. Six mutations were missense mutations located between exons 5 and 8. One mutation was a nonsense mutation in exon 6, and one mutation was a splicing mutation in intron 4, generating aberrant shorter p53 RNA(s). In three families, a mutation of the p53 gene was observed in the fibroblast cell line derived from the proband. However, the mutation was not found in affected relatives in two families and in the blood from the one individual, indicating that the mutation probably occurred during cell culture in vitro. In four families, no mutation was observed. This study indicates that germ-line p53 mutations in LFS are mostly located between exons 5 and 8 and that approximately 50% of patients with LFS have no germ-line mutations in the coding region of the p53 gene.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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

  1. Birch J. M., Hartley A. L., Tricker K. J., Prosser J., Condie A., Kelsey A. M., Harris M., Jones P. H., Binchy A., Crowther D. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994 Mar 1;54(5):1298–1304. [PubMed] [Google Scholar]
  2. Brugières L., Gardes M., Moutou C., Chompret A., Meresse V., Martin A., Poisson N., Flamant F., Bonaïti-Pellié C., Lemerle J. Screening for germ line p53 mutations in children with malignant tumors and a family history of cancer. Cancer Res. 1993 Feb 1;53(3):452–455. [PubMed] [Google Scholar]
  3. Børresen A. L., Andersen T. I., Garber J., Barbier-Piraux N., Thorlacius S., Eyfjörd J., Ottestad L., Smith-Sørensen B., Hovig E., Malkin D. Screening for germ line TP53 mutations in breast cancer patients. Cancer Res. 1992 Jun 1;52(11):3234–3236. [PubMed] [Google Scholar]
  4. Caron de Fromentel C., Soussi T. TP53 tumor suppressor gene: a model for investigating human mutagenesis. Genes Chromosomes Cancer. 1992 Jan;4(1):1–15. doi: 10.1002/gcc.2870040102. [DOI] [PubMed] [Google Scholar]
  5. Diller L., Kassel J., Nelson C. E., Gryka M. A., Litwak G., Gebhardt M., Bressac B., Ozturk M., Baker S. J., Vogelstein B. p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol. 1990 Nov;10(11):5772–5781. doi: 10.1128/mcb.10.11.5772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  7. Eeles R. A. Predictive testing for germline mutations in the p53 gene: are all the questions answered? Eur J Cancer. 1993;29A(10):1361–1365. doi: 10.1016/0959-8049(93)90001-v. [DOI] [PubMed] [Google Scholar]
  8. Eeles R. A., Warren W., Knee G., Bartek J., Averill D., Stratton M. R., Blake P. R., Tait D. M., Lane D. P., Easton D. F. Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings. Oncogene. 1993 May;8(5):1269–1276. [PubMed] [Google Scholar]
  9. Felix C. A., Nau M. M., Takahashi T., Mitsudomi T., Chiba I., Poplack D. G., Reaman G. H., Cole D. E., Letterio J. J., Whang-Peng J. Hereditary and acquired p53 gene mutations in childhood acute lymphoblastic leukemia. J Clin Invest. 1992 Feb;89(2):640–647. doi: 10.1172/JCI115630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Felix C. A., Strauss E. A., D'Amico D., Tsokos M., Winter S., Mitsudomi T., Nau M. M., Brown D. L., Leahey A. M., Horowitz M. E. A novel germline p53 splicing mutation in a pediatric patient with a second malignant neoplasm. Oncogene. 1993 May;8(5):1203–1210. [PubMed] [Google Scholar]
  11. Frebourg T., Barbier N., Kassel J., Ng Y. S., Romero P., Friend S. H. A functional screen for germ line p53 mutations based on transcriptional activation. Cancer Res. 1992 Dec 15;52(24):6976–6978. [PubMed] [Google Scholar]
  12. Frebourg T., Friend S. H. Cancer risks from germline p53 mutations. J Clin Invest. 1992 Nov;90(5):1637–1641. doi: 10.1172/JCI116034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Frebourg T., Kassel J., Lam K. T., Gryka M. A., Barbier N., Andersen T. I., Børresen A. L., Friend S. H. Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6413–6417. doi: 10.1073/pnas.89.14.6413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Futreal P. A., Barrett J. C., Wiseman R. W. An Alu polymorphism intragenic to the TP53 gene. Nucleic Acids Res. 1991 Dec 25;19(24):6977–6977. doi: 10.1093/nar/19.24.6977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Harvey D. M., Levine A. J. p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. Genes Dev. 1991 Dec;5(12B):2375–2385. doi: 10.1101/gad.5.12b.2375. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Iavarone A., Matthay K. K., Steinkirchner T. M., Israel M. A. Germ-line and somatic p53 gene mutations in multifocal osteogenic sarcoma. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4207–4209. doi: 10.1073/pnas.89.9.4207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ishioka C., Frebourg T., Yan Y. X., Vidal M., Friend S. H., Schmidt S., Iggo R. Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet. 1993 Oct;5(2):124–129. doi: 10.1038/ng1093-124. [DOI] [PubMed] [Google Scholar]
  21. Kovar H., Auinger A., Jug G., Müller T., Pillwein K. p53 mosaicism with an exon 8 germline mutation in the founder of a cancer-prone pedigree. Oncogene. 1992 Nov;7(11):2169–2173. [PubMed] [Google Scholar]
  22. Kuivaniemi H., Sabol C., Tromp G., Sippola-Thiele M., Prockop D. J. A 19-base pair deletion in the pro-alpha 2(I) gene of type I procollagen that causes in-frame RNA splicing from exon 10 to exon 12 in a proband with atypical osteogenesis imperfecta and in his asymptomatic mother. J Biol Chem. 1988 Aug 15;263(23):11407–11413. [PubMed] [Google Scholar]
  23. Law J. C., Strong L. C., Chidambaram A., Ferrell R. E. A germ line mutation in exon 5 of the p53 gene in an extended cancer family. Cancer Res. 1991 Dec 1;51(23 Pt 1):6385–6387. [PubMed] [Google Scholar]
  24. 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]
  25. Li F. P., Fraumeni J. F., Jr, Mulvihill J. J., Blattner W. A., Dreyfus M. G., Tucker M. A., Miller R. W. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988 Sep 15;48(18):5358–5362. [PubMed] [Google Scholar]
  26. Li F. P., Garber J. E., Friend S. H., Strong L. C., Patenaude A. F., Juengst E. T., Reilly P. R., Correa P., Fraumeni J. F., Jr Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. J Natl Cancer Inst. 1992 Aug 5;84(15):1156–1160. doi: 10.1093/jnci/84.15.1156. [DOI] [PubMed] [Google Scholar]
  27. Malkin D., Jolly K. W., Barbier N., Look A. T., Friend S. H., Gebhardt M. C., Andersen T. I., Børresen A. L., Li F. P., Garber J. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992 May 14;326(20):1309–1315. doi: 10.1056/NEJM199205143262002. [DOI] [PubMed] [Google Scholar]
  28. Malkin D., Li F. P., Strong L. C., Fraumeni J. F., Jr, Nelson C. E., Kim D. H., Kassel J., Gryka M. A., Bischoff F. Z., Tainsky M. A. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990 Nov 30;250(4985):1233–1238. doi: 10.1126/science.1978757. [DOI] [PubMed] [Google Scholar]
  29. Marx J. Learning how to suppress cancer. Science. 1993 Sep 10;261(5127):1385–1387. doi: 10.1126/science.8367721. [DOI] [PubMed] [Google Scholar]
  30. McIntyre J. F., Smith-Sorensen B., Friend S. H., Kassell J., Borresen A. L., Yan Y. X., Russo C., Sato J., Barbier N., Miser J. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol. 1994 May;12(5):925–930. doi: 10.1200/JCO.1994.12.5.925. [DOI] [PubMed] [Google Scholar]
  31. Metzger A. K., Sheffield V. C., Duyk G., Daneshvar L., Edwards M. S., Cogen P. H. Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7825–7829. doi: 10.1073/pnas.88.17.7825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  33. Morgenstern J. P., Land H. A series of mammalian expression vectors and characterisation of their expression of a reporter gene in stably and transiently transfected cells. Nucleic Acids Res. 1990 Feb 25;18(4):1068–1068. doi: 10.1093/nar/18.4.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Prives C., Manfredi J. J. The p53 tumor suppressor protein: meeting review. Genes Dev. 1993 Apr;7(4):529–534. doi: 10.1101/gad.7.4.529. [DOI] [PubMed] [Google Scholar]
  35. Sakuraba H., Eng C. M., Desnick R. J., Bishop D. F. Invariant exon skipping in the human alpha-galactosidase A pre-mRNA: Ag+1 to t substitution in a 5'-splice site causing Fabry disease. Genomics. 1992 Apr;12(4):643–650. doi: 10.1016/0888-7543(92)90288-4. [DOI] [PubMed] [Google Scholar]
  36. Sameshima Y., Tsunematsu Y., Watanabe S., Tsukamoto T., Kawa-ha K., Hirata Y., Mizoguchi H., Sugimura T., Terada M., Yokota J. Detection of novel germ-line p53 mutations in diverse-cancer-prone families identified by selecting patients with childhood adrenocortical carcinoma. J Natl Cancer Inst. 1992 May 6;84(9):703–707. doi: 10.1093/jnci/84.9.703. [DOI] [PubMed] [Google Scholar]
  37. Santibáez-Koref M. F., Birch J. M., Hartley A. L., Jones P. H., Craft A. W., Eden T., Crowther D., Kelsey A. M., Harris M. p53 germline mutations in Li-Fraumeni syndrome. Lancet. 1991 Dec 14;338(8781):1490–1491. doi: 10.1016/0140-6736(91)92303-j. [DOI] [PubMed] [Google Scholar]
  38. Scott R. J., Krummenacher F., Mary J. L., Weber W., Spycher M., Müller H. Vererbbare p53-Mutation bei einem Patienten mit Mehrfachtumoren: Bedeutung für die genetische Beratung. Schweiz Med Wochenschr. 1993 Jun 26;123(25):1287–1292. [PubMed] [Google Scholar]
  39. Sherratt T. G., Vulliamy T., Dubowitz V., Sewry C. A., Strong P. N. Exon skipping and translation in patients with frameshift deletions in the dystrophin gene. Am J Hum Genet. 1993 Nov;53(5):1007–1015. [PMC free article] [PubMed] [Google Scholar]
  40. Sidransky D., Tokino T., Helzlsouer K., Zehnbauer B., Rausch G., Shelton B., Prestigiacomo L., Vogelstein B., Davidson N. Inherited p53 gene mutations in breast cancer. Cancer Res. 1992 May 15;52(10):2984–2986. [PubMed] [Google Scholar]
  41. Srivastava S., Zou Z. Q., Pirollo K., Blattner W., Chang E. H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990 Dec 20;348(6303):747–749. doi: 10.1038/348747a0. [DOI] [PubMed] [Google Scholar]
  42. Sun F., Knebelmann B., Pueyo M. E., Zouali H., Lesage S., Vaxillaire M., Passa P., Cohen D., Velho G., Antignac C. Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young. J Clin Invest. 1993 Sep;92(3):1174–1180. doi: 10.1172/JCI116687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Toguchida J., Yamaguchi T., Dayton S. H., Beauchamp R. L., Herrera G. E., Ishizaki K., Yamamuro T., Meyers P. A., Little J. B., Sasaki M. S. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med. 1992 May 14;326(20):1301–1308. doi: 10.1056/NEJM199205143262001. [DOI] [PubMed] [Google Scholar]
  44. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  45. Warneford S. G., Witton L. J., Townsend M. L., Rowe P. B., Reddel R. R., Dalla-Pozza L., Symonds G. Germ-line splicing mutation of the p53 gene in a cancer-prone family. Cell Growth Differ. 1992 Nov;3(11):839–846. [PubMed] [Google Scholar]
  46. Weeks D. E., Lange K. The affected-pedigree-member method of linkage analysis. Am J Hum Genet. 1988 Feb;42(2):315–326. [PMC free article] [PubMed] [Google Scholar]
  47. Weil D., Bernard M., Combates N., Wirtz M. K., Hollister D. W., Steinmann B., Ramirez F. Identification of a mutation that causes exon skipping during collagen pre-mRNA splicing in an Ehlers-Danlos syndrome variant. J Biol Chem. 1988 Jun 25;263(18):8561–8564. [PubMed] [Google Scholar]
  48. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

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