TP53, hChk2, and the Li-Fraumeni Syndrome

  • Jenny Varley
Part of the Methods in Molecular Biology™ book series (MIMB, volume 222)

Abstract

In 1969 Li and Fraumeni (1,2) reported a systematic epidemiologic study of the incidence of cancers in relatives of children with rhabdomyosarcoma (RMS). They noted five families of 648 probands in which a sib or cousin was also affected by sarcoma, and furthermore prospective studies of four of these families revealed a strikingly increased frequency of several types of cancer. Twenty-four families were subsequently studied in detail by the same groups (3), and a definition of what has now been termed Li-Fraumeni syndrome (LFS) was derived. Classic LFS is defined by a proband with a sarcoma aged under 45 years with a first degree relative with any cancer under 45 and an additional first- or second-degree relative in the same lineage with any cancer under 45, or a sarcoma at any age. This definition is still widely used, but other groups have introduced more relaxed definitions taking into account a more extensive knowledge of the range of tumors identified in families, and the ages of onset. One of the most widely used was defined by Birch et al. (4) as Li-Fraumeni-like (LFL) and is a proband with any childhood tumor, or sarcoma, brain tumor, or adrenocortical tumor under 45 years, plus a first- or second-degree relative with a typical LFS tumor at any age and another first- or second-degree relative with any cancer under the age of 60. In all the discussions that follow, the above definitions of LFS and LFL will be used. Typical LFS tumors in this context include sarcomas, brain and breast tumors, and childhood adrenocortical carcinoma.

References

  1. 1.
    Li, F. P. and Fraumeni, J. F. (1969) Rhabdomyosarcoma in children; epidemiologic study and identification of a cancer family syndrome. J. Natl. Cancer. Inst. 43, 1365–1373.PubMedGoogle Scholar
  2. 2.
    Li, F. P. and Fraumeni, J. F. (1969) Soft-tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann. Intern. Med. 71, 747–752.PubMedGoogle Scholar
  3. 3.
    Li, F. P., Fraumeni, J. F., Mulvihill, J. J., et al. (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res. 48, 5358–5362.PubMedGoogle Scholar
  4. 4.
    Birch, J. M., Hartley, A. L., Tricker, K. J., et al. (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 54, 1298–1304.PubMedGoogle Scholar
  5. 5.
    Malkin, D., Li, F. P., Strong, L. C., et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238.PubMedCrossRefGoogle Scholar
  6. 6.
    Santibanez-Koref, M. F., Birch, J. M., Hartley, A. L., et al. (1991) p53 germline mutations in Li-Fraumeni syndrome. Lancet 338, 1490–1491.PubMedCrossRefGoogle Scholar
  7. 7.
    Frebourg, T., Barbier, N., Yan, Y., et al. (1995) Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am. J. Hum. Genet. 56, 608–615.PubMedGoogle Scholar
  8. 8.
    Varley, J. M., Evans, D. G. R., and Birch, J. M. (1997) Li-Fraumeni syndrome—a molecular and clinical review. Br. J. Cancer 76, 1–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Varley, J. M., McGown, G., Thorncroft, M., et al. (1997) Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. 57, 3245–3252.PubMedGoogle Scholar
  10. 10.
    Diller, L., Sexsmith, E., Gottlieb, A., Li, F. P., and Malkin, D. (1995) Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J. Clin. Invest. 95, 1606–1611.PubMedCrossRefGoogle Scholar
  11. 11.
    Toguchida, J., Yamaguchi, T., Dayton, S. H., et al. (1992) Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N. Engl. J. Med. 326, 1301–1308.PubMedCrossRefGoogle Scholar
  12. 12.
    McIntyre, J. F., Smith-Sorensen, B., Friend, S. H., et al. (1994) Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J. Clin. Oncol. 12, 925–930.PubMedGoogle Scholar
  13. 13.
    Li, Y.-J., Sanson, M., Hoang-Xuan, K., et al. (1995) Incidence of germ-line p53 mutations in patients with gliomas. Int. J. Cancer 64, 383–387.PubMedCrossRefGoogle Scholar
  14. 14.
    Kyritsis, A. P., Bondy, M. L., Xiao, M., et al. (1994) Germline p53 mutations in subsets of glioma patients. J. Natl. Cancer Inst. 86, 344–349.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen, P., Iavarone, A., Fick, J., Edwards, M., Prados, M., and Israel, M. A. (1995) Constitutional p53 mutations associated with brain tumors in young adults. Cancer Genet. Cytogenet. 82, 106–115.PubMedCrossRefGoogle Scholar
  16. 16.
    Børresen, A.-L., Andersen, T. I., Garber, J., et al. (1992) Screening for germ line TP53 mutations in breast cancer patients. Cancer Res. 52, 3234–3236.PubMedGoogle Scholar
  17. 17.
    Prosser, J., Porter, D., Coles, C., et al. (1992) Constitutional p53 mutation in a non-Li-Fraumeni cancer family. Br. J. Cancer 65, 527–528.PubMedCrossRefGoogle Scholar
  18. 18.
    Sidransky, D., Tokino, T., Helzlsouer, K., et al. (1992) Inherited p53 gene mutations in breast cancer. Cancer Res. 52, 2984–2986.PubMedGoogle Scholar
  19. 19.
    Varley, J. M., McGown, G., Thorncroft, M., et al. (1999) Are there low penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. Am. J. Hum. Genet. 65, 995–1006.PubMedCrossRefGoogle Scholar
  20. 20.
    Wagner, J., Portwine, C., Rabin, K., Leclerc, J.-M., Narod, S. A., and Malkin, D. (1994) High frequency of germline p53 mutations in childhood adrenocortical cancer. J. Natl. Cancer Inst. 86, 1707–1710.PubMedCrossRefGoogle Scholar
  21. 21.
    Ribeiro, R. C., Sandrini, F., Figueiredo, B., et al. (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc. Natl. Acad. Sci. USA 98, 9330–9335.PubMedCrossRefGoogle Scholar
  22. 22.
    Malkin, D., Jolly, K. W., Barbier, N., et al. (1992) Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N. Engl. J. Med. 326, 1309–1315.PubMedCrossRefGoogle Scholar
  23. 23.
    Mazoyer, S., Lalle, P., Moyret-Lalle, C., et al. (1994) Two germ-line mutations affecting the same nucleotide at codon 257 of p53 gene, a rare site for mutations. Oncogene 9, 1237–1239.PubMedGoogle Scholar
  24. 24.
    Shiseki, M., Nishikawa, R., Yamamoto, H., et al. (1993) Germ-line p53 mutation is uncommon in patients with triple primary cancers. Cancer Lett. 73, 51–57.PubMedCrossRefGoogle Scholar
  25. 25.
    Iavarone, A., Matthay, K. K., Steinkirchner, T. M., and Israel, M.A. (1992) Germ-line and somatic p53 mutations in multifocal osteogenic sarcoma. Proc. Natl. Acad. Sci. USA 89, 4207–4209.PubMedCrossRefGoogle Scholar
  26. 26.
    Quesnel, S., Verselis, S., Portwine, C., et al. (1999) p53 compound heterozygosity in a severely affected child with Li-Fraumeni Syndrome. Oncogene 18, 3970–3978.PubMedCrossRefGoogle Scholar
  27. 27.
    Gallo, O., Sardi, I., Pepe, G., et al. (1999) Multiple primary tumors of the upper aerodigestive tract: is there a role for constitutional mutations in the p53 gene. Int. J. Cancer 82, 180–186.PubMedCrossRefGoogle Scholar
  28. 28.
    Bot, F. J., Sleddens, H. F., and Dinjens, W. N. (1998) Molecular assessment of clonality leads to the identification of a new germ line TP53 mutation associated with malignant cystosarcoma phylloides and soft tissue sarcoma. Diagn. Mol. Pathol. 7, 295–301.PubMedCrossRefGoogle Scholar
  29. 29.
    Speiser, P., Gharehbaghi-Schnell, E., Eder, S., et al. (1996) A constitutional de novo mutation in exon 8 of the p53 gene in a patient with multiple primary malignancies. Br. J. Cancer 74, 269–273.PubMedCrossRefGoogle Scholar
  30. 30.
    Gutierrez, M. I., Bhatia, K. G., Barreiro, C., et al. (1994) A de novo p53 germline mutation affecting codon 151 in a six year old child with multiple tumors. Hum. Mol. Genet. 3, 2247–2248.PubMedCrossRefGoogle Scholar
  31. 31.
    Soussi, T., Caron de Fromentel, C., and May, P. (1990) Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5, 945–952.Google Scholar
  32. 32.
    Birch, J. M., Alston, R. D., McNally, R. J. Q., et al. (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20, 4621–4628.PubMedCrossRefGoogle Scholar
  33. 33.
    Birch, J. M., Blair, V., Kelsey, A. M., et al. (1998) Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni Syndrome. Oncogene 17, 1061–1068.PubMedCrossRefGoogle Scholar
  34. 34.
    Varley, J. M., Attwooll, C., White, G., et al. (2001) Characterisation of germline TP53 splicing mutations and their genetic and functional analysis. Oncogene 20, 2647–2654.PubMedCrossRefGoogle Scholar
  35. 35.
    Casey, G., Lopez, M. E., Ramos, J. C., et al. (1996) DNA sequence analysis of exons 2 though 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies. Oncogene 13, 1971–1981.PubMedGoogle Scholar
  36. 36.
    Bergh, J., Norberg, T., Sjogren, S., Lindgren, A., and Holmberg, L. (1995) Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nature Med. 1, 1029–1034.PubMedCrossRefGoogle Scholar
  37. 37.
    Verselis, S. J., Rheinwald, J. G., Fraumeni, J. F., and Li, F. P. (2000) Novel p53 splice site mutations in three families with Li-Fraumeni syndrome. Oncogene 19, 4230–4235.PubMedCrossRefGoogle Scholar
  38. 38.
    Attwooll, C. L., McGown, G., Thorncroft, M., Stewart, F. J., Birch, J. M., and Varley, J. M. (2002) Identification of a rare polymorphism in the human TP53 promoter. Cancer Genet. Cytogenet. 135, 165–172.PubMedCrossRefGoogle Scholar
  39. 39.
    Varley, J. M., Thorncroft, M., McGown, G., et al. (1997) A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. Oncogene 14, 865–871.PubMedCrossRefGoogle Scholar
  40. 40.
    Lane, D. P. (1992) p53, guardian of the genome. Nature 358, 15–16.PubMedCrossRefGoogle Scholar
  41. 41.
    Nichols, K. E., Malkin, D., Garber, J. E., Fraumeni, J. F., and Li, F. P. (2001) Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol. Biomarkers Prev. 10, 83–91.PubMedGoogle Scholar
  42. 42.
    Kleihues, P., Schäuble, B., zur Hausen, A., Estève, J., and Ohgaki, H. (1997) Tumors associated with p53 germline mutations. A synopsis of 91 families. Am. J. Pathol. 150, 1–13.PubMedGoogle Scholar
  43. 43.
    Wang, Q., Lasset, C., Sobol, H., and Ozturk, M. (1996) Evidence of a hereditary p53 syndrome. Int. J. Cancer 65, 554–557.PubMedCrossRefGoogle Scholar
  44. 44.
    Garber, J. E., Goldstein, A. M., Kantor, A. F., Dreyfus, M. G., Fraumeni, J. F., and Li, F. P. (1991) Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res. 51, 6094–6097.PubMedGoogle Scholar
  45. 45.
    Sameshima, Y., Tsunematsu, Y., Watanabe, S., et al. (1992) Detection of novel germ-line p53 mutations in diverse-cancer-prone families identified by screening patients with childhood adrenocortical carcinoma. J. Natl. Cancer Inst. 84, 703–707.PubMedCrossRefGoogle Scholar
  46. 46.
    Stolzenberg, M.-C., Brugières, L., Gardes, M., et al. (1994) Germ-line exclusion of a single p53 allele by premature termination of translation in a Li-Fraumeni family. Oncogene 9, 2799–2804.PubMedGoogle Scholar
  47. 47.
    Felix, C. A., Strauss, E. A., D’Amico, D., et al. (1993) A novel germline p53 splicing mutation in a pediatric patient with a second malignant neoplasm. Oncogene 8, 1203–1210.PubMedGoogle Scholar
  48. 48.
    Warneford, S. G., Witton, L. J., Townsend, M. L., et al. (1992) Germ-line splicing mutation of the p53 gene in a cancer-prone family. Cell Growth Differ. 3, 839–846.PubMedGoogle Scholar
  49. 49.
    Grayson, G. H., Moore, S., Schneider, B. G., Saldivar, V., and Hensel, C. H. (1994) Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. Am. J. Pediatr. Hematol. Oncol. 16, 341–347.PubMedGoogle Scholar
  50. 50.
    Lubbe, J., von Ammon, K., Watanabe, K., Hegi, M. E., and Kleihues, P. (1995) Familial brain tumour syndrome associated with a p53 germline deletion at codon 236. Brain Pathol. 5, 15–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Strauss, E. A., Hosler, M. R., Herzog, P., Salhany, K., Louie, R., and Felix, C. A. (1995) Complex replication error causes p53 mutation in a Li-Fraumeni family. Cancer Res. 55, 3237–3241.PubMedGoogle Scholar
  52. 52.
    Bardeesy, N., Falkoff, D., Petruzzi, M.-J., et al. (1994) Anaplastic Wilms’ tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nature Genet. 7, 91–97.PubMedCrossRefGoogle Scholar
  53. 53.
    Giunta, C., Youil, R., Venter, D., et al. (1996) Rapid diagnosis of germline p53 mutation using the enzyme mismatch cleavage method. Diagn. Mol. Pathol. 5, 265–270.PubMedCrossRefGoogle Scholar
  54. 54.
    Moutou, C., Le Bihan, C., Chompret, A., et al. (1996) Genetic transmission of susceptibility to cancer in families of children with soft tissue sarcomas. Cancer 78, 1483–1491.PubMedCrossRefGoogle Scholar
  55. 55.
    Sedlacek, Z., Kodet, R., Kriz, V., et al. (1998) Two Li-Fraumeni syndrome families with novel germline p53 mutations: loss of the wild type p53 allele in only 50% of tumours. Br. J. Cancer 77, 1034–1039.PubMedCrossRefGoogle Scholar
  56. 56.
    Pivnick, E. K., Furman, W. L., Velagaleti, G. V. N., Jenkins, J. J., Chase, N. A., and Ribiero, R. C. (1998) Simultaneous adrenocortical carcinoma and ganglioneuroblastoma in a child with Turner syndrome and germline p53 mutation. J. Med. Genet. 35, 328–332.PubMedCrossRefGoogle Scholar
  57. 57.
    Chompret, A., Brugieres, L., Ronsin, M., et al. (2000) p53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer 82, 1932–1937.PubMedCrossRefGoogle Scholar
  58. 58.
    Vital, A., Bringuier, P.-P., Huang, H., et al. (1998) Astrocytomas and choroid plexus tumors in two families with identical p53 germline mutations. J. Neuropathol. Exp. Neurol. 57, 1061–1069.PubMedCrossRefGoogle Scholar
  59. 59.
    Yonemoto, T., Tatezaki, S.-I., Ishii, T., Satoh, T., and Inoue, M. (1999) Two cases of osteosarcoma occurring as second malignancy of childhood cancer. Anticancer Res. 19, 5563–5566.PubMedGoogle Scholar
  60. 60.
    Bougeard, G., Limacher, J.-M., Martin, C., et al. (2001) Detection of 11 germline inactivating TP53 mutations and absence of TP63 and hCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. J. Med. Genet. 38, 253–256.PubMedCrossRefGoogle Scholar
  61. 61.
    LeBihan, C., Moutou, C., Brugières, L., Feunteun, J., and Bonaïti-Pellié, C. (1995) ARCAD: a method for estimating age-dependent disease risk associated with mutation carrier status from family data. Genet. Epidem. 12, 13–25.CrossRefGoogle Scholar
  62. 62.
    Marigo, C., Muller, H., and Davies, J. N. P. (1968) Survey of cancer in children admitted to a Brazilian charity hospital. J. Natl. Cancer Inst. 43, 1231–1240.Google Scholar
  63. 63.
    Sandrini, R., Ribeiro, R. C., and DeLacerda, L. (1997) Childhood adrenocortical tumors. J. Clin. Endocrinol. Metab. 82, 2027–2031.PubMedCrossRefGoogle Scholar
  64. 64.
    Prosser, J., Elder, P. A., Condie, A., MacFadyen, I., Steel, C. M., and Evans, H. J. (1991) Mutations in p53 do not account for heritable breast cancer: A study in five affected families. Br. J. Cancer 63, 181–184.PubMedCrossRefGoogle Scholar
  65. 65.
    Huusko, P., Castren, K., Launonen, V., et al. (1999) Germ-line TP53 mutations in Finnish cancer families exhibiting features of the Li-Fraumeni syndrome and negative for BRCA1 and BRCA2. Cancer Genet. Cytogenet. 112, 9–14.PubMedCrossRefGoogle Scholar
  66. 66.
    Rapakko, K., Allinen, M., Syrjakoski, K., et al. (2001) Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites. Br. J. Cancer 84, 116–119.PubMedCrossRefGoogle Scholar
  67. 67.
    Sun, X.-F., Johannsson, O., Hakansson, S., et al. (1996) A novel p53 germline alteration identified in a late onset breast cancer kindred. Oncogene 13, 407–411.PubMedGoogle Scholar
  68. 68.
    Lalloo, F., Varley, J., Ellis, D., et al. (2002) Family history is predictive of pathogenic, high penetrance mutations in BRCA1, BRCA2 and TP53 in early-onset breast cancer. Lancet in pressGoogle Scholar
  69. 69.
    Burt, E. C., McGown, G., Thorncroft, M., James, L. A., Birch, J. M., and Varley, J. M. (1999) Exclusion of the genes CDKN2 and PTEN as causative gene defects in Li-Fraumeni Syndrome. Br. J. Cancer 80, 9–10.PubMedCrossRefGoogle Scholar
  70. 70.
    Brown, L. T., Sexsmith, E., and Malkin, D. (2000) Identification of a novel PTEN intronic deletion in Li-Fraumeni Syndrome and its effect on RNA processing. Cancer Genet. Cytogenet. 123, 65–68.PubMedCrossRefGoogle Scholar
  71. 71.
    Portwine, C., Lees, J., Verselis, S., Li, F. P., and Malkin, D. (2000) Absence of germline p16(INK4a) alterations in p53 wild type Li-Fraumeni syndrome families. J. Med. Genet. 37, E11.CrossRefGoogle Scholar
  72. 72.
    Stone, J. G., Eeles, R. A., Sodha, N., Murday, V., Sheriden, E., and Houlston, R. S. (1999) Analysis of Li-Fraumeni Syndrome and Li-Fraumeni-like families for germline mutations in Bcl10. Cancer Lett. 147, 181–185.PubMedCrossRefGoogle Scholar
  73. 73.
    Bell, D. W., Varley, J. M., Szydlo, T. E., et al. (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni Syndrome. Science 286, 2528–2531.PubMedCrossRefGoogle Scholar
  74. 74.
    Lee, S. B., Kim, S. H., Bell, D. W., et al. (2001) Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 61, 8062–8067.PubMedGoogle Scholar
  75. 75.
    Sodha, N., Williams, R., Mangion, J., et al. (2000) Screening hCHK2 for mutations. Science 289, 359a.CrossRefGoogle Scholar
  76. 76.
    Allinen, M., Huusko, P., Mantyniemi, S., Launonen, V., and Winqvist, R. (2001) Mutation analysis of the CHK2 gene in families with hereditary breast cancer. Br. J. Cancer 85, 209–212.PubMedCrossRefGoogle Scholar
  77. 77.
    Wu, X., Webster, S. R., and Chen, J. (2001) Characterization of tumor-associated Chk2 mutations. J. Biol. Chem. 276, 2971–2974.PubMedCrossRefGoogle Scholar
  78. 78.
    Falck, J., Lukas, C., Protopopova, M., Lukas, J., Selivanova, G., and Bartek, J. (2001) Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene 20, 5503–5510.PubMedCrossRefGoogle Scholar
  79. 79.
    Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J., and Lukas, J. (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842–847.PubMedCrossRefGoogle Scholar
  80. 80.
    Vahteristo, P., Tamminen, A., Karvinen, P., et al. (2001) p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 61, 5718–5722.PubMedGoogle Scholar
  81. 81.
    Lee, C.-H. and Chung, J. H. (2001) The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation. J. Biol. Chem. 276, 30537–30541.PubMedCrossRefGoogle Scholar
  82. 82.
    Rhind, N. and Russell, P. (2000) Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways. J. Cell Sci. 113, 3889–3896.PubMedGoogle Scholar
  83. 83.
    Zhou, B.-B. S. and Elledge, S. J. (2000) The DNA damage response: putting checkpoints into perspective. Nature 408, 433–439.PubMedCrossRefGoogle Scholar
  84. 84.
    Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y., Tamai, K., and Elledge, S. J. (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl. Acad. Sci. USA 97, 10389–10394.PubMedCrossRefGoogle Scholar
  85. 85.
    Chehab, N. H., Malikzay, A., Appel, M., and Halazonetis, T. D. (2000) Chk2/hCds1 functions as a DNA damage checkpoint in G1 by stabilizing p53. Genes Dev. 14, 278–288.PubMedGoogle Scholar
  86. 86.
    Xie, G., Habbersett, R. C., Jia, Y., et al. (1998) Requirements for the p53 and ATM gene product in the regulation of G1/S and S phase checkpoints. Oncogene 16, 721–736.PubMedCrossRefGoogle Scholar
  87. 87.
    Papadopoulos, N., Nicolaides, N. C., Liu, B., et al. (1995) Mutations of GTBP in genetically unstable cells. Science 268, 1915–1917.PubMedCrossRefGoogle Scholar
  88. 88.
    Lettieri, T., Marra, G., Aquilina, G., et al. (1999) Effect of hMSH6 cDNA expression on the phenotype of mismatch repair-deficient colon cancer cell line HCT15. Carcinogenesis 20, 373–382.PubMedCrossRefGoogle Scholar
  89. 89.
    Lee, J.-S., Collins, K. M., Brown, A. L., Lee, C.-H., and Chung, J. H. (2000) hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201–204.PubMedCrossRefGoogle Scholar
  90. 90.
    Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., and Qin, J. (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Jenny Varley
    • 1
  1. 1.CR-UK Department of Cancer GeneticsPaterson Institute of Cancer ResearchManchesterUK

Personalised recommendations