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Molecular Pathogenesis of Human Cancer

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Abstract

Cancer represents a significant health problem worldwide. The successful curative treatment of almost every form of this disease depends on early diagnosis and, in the case of solid tumors, surgical resection with or without adjuvant therapy. Intensive research efforts during the last several decades have increased our understanding of carcinogenesis and have identified a genetic basis for the multistep process of cancer development (1 –3). In several human tumor systems, specific genetic alterations have been shown to correlate with well-defined histopatho-logic stages of tumor development and progression (4,5). Although the significance of mutations to the etiological mechanisms of tumor development has been debated, a causal role for such genetic lesions is now commonly accepted for many human tumors. Thus, genetic lesions represent an integral part of the processes of neoplastic transformation, tumorigenesis, and tumor progression, and as such, they represent potentially valuable markers for cancer detection and staging (6,7). Through the application of specific and sensitive molecular methodologies, the clinical laboratory of the future will be able to effectively screen populations at high risk for the development of cancer, potentially impacting the early detection and diagnosis of human cancers. In addition, development of new molecular diagnostic assays will expand the ability of clinicians to accurately stage tumor development, monitor progression of metastatic disease, and evaluate therapeutic outcome, facilitating the application of effective intervention strategies in the treatment of human tumors.

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References

  1. Foulds, L. The natural history of cancer. J. Chronic Dis. 8:2–37, 1958.

    Article  CAS  PubMed  Google Scholar 

  2. Weinberg, R. A. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 49:3713–3721, 1989.

    CAS  PubMed  Google Scholar 

  3. Bishop, J. M. Molecular themes in oncogenesis. Cell 64:235–248, 1991.

    Article  CAS  PubMed  Google Scholar 

  4. Vogelstein, B., Fearon, E. R., Hamilton, S. R., et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319:525–532, 1988.

    Article  CAS  PubMed  Google Scholar 

  5. Fearon, E. R. and Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61:759–767, 1990.

    Article  CAS  PubMed  Google Scholar 

  6. Mao, L. and Sidransky, D. Cancer screening based on genetic alterations in human tumors. Cancer Res. 54:1939s–1940s, 1994.

    CAS  PubMed  Google Scholar 

  7. Sidransky, D. Molecular markers in cancer: can we make better predictions? Int. J. Cancer 64:1–2, 1995.

    Article  CAS  PubMed  Google Scholar 

  8. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194:23–28, 1976.

    Article  CAS  PubMed  Google Scholar 

  9. Lengauer, C., Kinzler, K. W., and Vogelstein, B. Genetic instabilities in human cancers. Nature 396:643–649, 1998.

    Article  CAS  PubMed  Google Scholar 

  10. Renan, M. J. How many mutations are required for tumorigenesis? Implications from human cancer data. Mol. Carcinog. 7:139–146, 1993.

    Article  CAS  PubMed  Google Scholar 

  11. Cairns, J. Mutation selection and the natural history of cancer. Nature 255:197–200, 1975.

    Article  CAS  PubMed  Google Scholar 

  12. Loeb, K. R. and Loeb, L. A. Significance of multiple mutations in cancer. Carcinogenesis 21:379–385, 2000.

    Article  CAS  PubMed  Google Scholar 

  13. Cohen, A. M., Minsky, B. D., and Schilsky, R. L. Cancer of the colon, in Cancer: Principles and Practice of Oncology, 5th ed., DeVita, V. T., Hellman, S., and Rosenberg, S. A., eds., Lippincott–Raven, Philadelphia, 1997, pp. 1144–1197.

    Google Scholar 

  14. Kinzler, K. W. and Vogelstein, B. Colorectal tumors, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 1033–1062.

    Google Scholar 

  15. Sidransky, D. Molecular markers in cancer diagnosis. J. Natl. Cancer Inst. Monogr. 17:27–29, 1995.

    PubMed  Google Scholar 

  16. Crow, J. F. The high spontaneous mutation rate: is it a health risk? Proc. Natl. Acad. Sci. USA 94:8380–8386, 1997.

    Article  CAS  PubMed  Google Scholar 

  17. Cairns, J. Mutation and cancer: the antecedents to our studies of adaptive mutation. Genetics 148:1433–1440, 1998.

    CAS  PubMed  Google Scholar 

  18. Ruddon, R. W. Cancer Biology, 3rd ed., Oxford University Press, New York, 1995.

    Google Scholar 

  19. Fisher, J. C. Multiple-mutation theory of carcinogenesis. Nature 181:651–652, 1958.

    Article  CAS  PubMed  Google Scholar 

  20. Fisher, J. C. and Hollomon, J. H. A hypothesis for the origin of cancer foci. Cancer 4:916–918, 1951.

    Article  CAS  PubMed  Google Scholar 

  21. Strong, L. C. The induction of mutations by a carcinogen. Br. J. Cancer 3:97–108, 1949.

    CAS  PubMed  Google Scholar 

  22. Berenblum, I. and Shubik, P. An experimental study of the initiating stage of carcinogenesis, and re-examination of the somatic cell mutation theory of cancer. Br. J. Cancer 3:109–118, 1949.

    CAS  PubMed  Google Scholar 

  23. Nowell, P. C. and Hungerford, D. A. Chromosome studies on normal and leukemic human leukocytes. J. Natl. Cancer Inst. 25:85–109, 1960.

    CAS  PubMed  Google Scholar 

  24. Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. [letter]. Nature 243:290–293, 1973.

    Article  CAS  PubMed  Google Scholar 

  25. Albertson, D. G., Collins, C., McCormick, F., and Gray, J. W. Chromosome aberrations in solid tumors. Nat. Genet. 34:369–376, 2003.

    Article  CAS  PubMed  Google Scholar 

  26. Hussain, S. P. and Harris, C. C. Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res. 58:4023–4037, 1998.

    CAS  PubMed  Google Scholar 

  27. Perou, C. M., Sorlie, T., Eisen, M. B., et al. Molecular portraits of human breast tumours. Nature 406:747–752, 2000.

    Article  CAS  PubMed  Google Scholar 

  28. Hedenfalk, I., Ringner, M., Ben-Dor, A., et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc. Natl. Acad. Sci. USA 100:2532–2537, 2003.

    Article  CAS  PubMed  Google Scholar 

  29. Chung, C. H., Parker, J. S., Karaca, G., et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5:489–500, 2004.

    Article  CAS  PubMed  Google Scholar 

  30. Meyerson, M., Franklin, W. A., and Kelley, M. J. Molecular classification and molecular genetics of human lung cancers. Semin. Oncol. 31:4–19, 2004.

    Article  CAS  PubMed  Google Scholar 

  31. Hoang, C. D., D’Cunha, J., Tawfic, S. H., Gruessner, A. C., Kratzke, R. A., and Maddaus, M. A. Expression profiling of non-small cell lung carcinoma identifies metastatic genotypes based on lymph node tumor burden. J. Thorac. Cardiovasc. Surg. 127:1332–1341, 2004; discussion 1342.

    Article  CAS  PubMed  Google Scholar 

  32. Warner, G. C., Reis, P. P., Jurisica, I., et al. Molecular classification of oral cancer by cDNA microarrays identifies overexpressed genes correlated with nodal metastasis. Int. J. Cancer 110:857–868, 2004.

    Article  CAS  PubMed  Google Scholar 

  33. Cleator, S. and Ashworth, A. Molecular profiling of breast cancer: clinical implications. Br. J. Cancer 90:1120–1124, 2004.

    Article  CAS  PubMed  Google Scholar 

  34. Troester, M. A., Hoadley, K. A., Sorlie, T., et al. Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 64:4218–4226, 2004.

    Article  CAS  PubMed  Google Scholar 

  35. Armitage, P. and Doll, R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br. J. Cancer 11:161–169, 1957.

    CAS  PubMed  Google Scholar 

  36. Knudson, A. G., Jr. Mutation and cancer: statistical study of retinoblas-toma. Proc. Natl. Acad. Sci. USA 68:820–823, 1971.

    Article  PubMed  Google Scholar 

  37. Baylin, S. B. Mechanisms underlying epigenetically mediated gene silencing in cancer. Semin. Cancer Biol. 12:331–337, 2002.

    Article  CAS  PubMed  Google Scholar 

  38. Herman, J. G. and Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349:2042–2054, 2003.

    Article  CAS  PubMed  Google Scholar 

  39. Fazzari, M. J. and Greally, J. M. Epigenomics: beyond CpG islands. Nat. Rev. Genet. 5:446–455, 2004.

    Article  CAS  PubMed  Google Scholar 

  40. Jackson, A. L. and Loeb, L. A. The mutation rate and cancer. Genetics 148:1483–1493, 1998.

    CAS  PubMed  Google Scholar 

  41. Loeb, L. A. A mutator phenotype in cancer. Cancer Res. 61:3230–3239, 2001.

    CAS  PubMed  Google Scholar 

  42. Loeb, L. A. and Christians, F. C. Multiple mutations in human cancers. Mutat. Res. 350:279–286, 1996.

    PubMed  Google Scholar 

  43. Perucho, M. Cancer of the microsatellite mutator phenotype. Biol. Chem. 377:675–684, 1996.

    CAS  PubMed  Google Scholar 

  44. Orr-Weaver, T. L. and Weinberg, R. A. A checkpoint on the road to cancer. Nature 392:223–224, 1998.

    Article  CAS  PubMed  Google Scholar 

  45. Christians, F. C., Newcomb, T. G., and Loeb, L. A. Potential sources of multiple mutations in human cancers. Prev. Med. 24:329–332, 1995.

    Article  CAS  PubMed  Google Scholar 

  46. Friedberg, E. C., McDaniel, L. D., and Schultz, R. A. The role of endogenous and exogenous DNA damage and mutagenesis. Curr. Opin. Genet. Dev. 14:5–10, 2004.

    Article  CAS  PubMed  Google Scholar 

  47. Sancar, A., Lindsey-Boltz, L. A., Unsal-Kaccmaz, K., and Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73:39–85, 2004.

    Article  CAS  PubMed  Google Scholar 

  48. Cooper, D. N., and Youssoufian, H. The CpG dinucleotide and human genetic disease. Hum. Genet. 78:151–155, 1988.

    Article  CAS  PubMed  Google Scholar 

  49. Goyette, M. C., Cho, K., Fasching, C. L., et al. Progression of col-orectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol. Cell. Biol. 12:1387–1395, 1992.

    CAS  PubMed  Google Scholar 

  50. Duesberg, P., Rausch, C., Rasnick, D., and Hehlmann, R. Genetic instability of cancer cells is proportional to their degree of aneu-ploidy. Proc. Natl. Acad. Sci. USA 95:13,692–13,697, 1998.

    Article  CAS  Google Scholar 

  51. Strauss, B. S. Hypermutability in carcinogenesis. Genetics 148:1619–1626, 1998.

    CAS  PubMed  Google Scholar 

  52. Sieber, O. M., Heinimann, K., and Tomlinson, I. P. Genomic instability —the engine of tumorigenesis? Nat. Rev. Cancer 3:701–708, 2003.

    Article  CAS  PubMed  Google Scholar 

  53. Hollstein, M., Shomer, B., Greenblatt, M., et al. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res. 24:141–146, 1996.

    Article  CAS  PubMed  Google Scholar 

  54. Moolgavkar, S. H. and Luebeck, E. G. Multistage carcinogenesis and the incidence of human cancer. Genes Chromosomes Cancer 38:302–306, 2003.

    Article  CAS  PubMed  Google Scholar 

  55. Boesen, J. J., Niericker, M. J., Dieteren, N., and Simons, J. W. How variable is a spontaneous mutation rate in cultured mammalian cells? Mutat. Res. 307:121–129, 1994.

    CAS  PubMed  Google Scholar 

  56. Eldridge, S. R. and Gould, M. N. Comparison of spontaneous muta-genesis in early-passage human mammary cells from normal and malignant tissues. Int. J. Cancer 50:321–324, 1992.

    Article  CAS  PubMed  Google Scholar 

  57. Wittenkeller, J. L., Storer, B., Bittner, G., and Schiller, J. H. Comparison of spontaneous and induced mutation rates in an immortalized human bronchial epithelial cell line and its tumorigenic derivative. Oncology 54:335–341, 1997.

    Article  CAS  PubMed  Google Scholar 

  58. Loeb, L. A. Mutator phenotype may be required for multistage car-cinogenesis. Cancer Res. 51:3075–3079, 1991.

    CAS  PubMed  Google Scholar 

  59. Loeb, L. A. Transient expression of a mutator phenotype in cancer cells. Science 277:1449–1450, 1997.

    Article  CAS  PubMed  Google Scholar 

  60. Richards, B., Zhang, H., Phear, G., and Meuth, M. Conditional mutator phenotypes in hMSH2-deficient tumor cell lines. Science 277:1523–1526, 1997.

    Article  CAS  PubMed  Google Scholar 

  61. Bhattacharyya, N. P., Skandalis, A., Ganesh, A., Groden, J., and Meuth, M. Mutator phenotypes in human colorectal carcinoma cell lines. Proc. Natl. Acad. Sci. USA 91:6319–6323, 1994.

    Article  CAS  PubMed  Google Scholar 

  62. Eshleman, J. R., Lang, E. Z., Bowerfind, G. K., et al. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10:33–37, 1995.

    CAS  PubMed  Google Scholar 

  63. Glaab, W. E. and Tindall, K. R. Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. Carcinogenesis 18:1–8, 1997.

    Article  CAS  PubMed  Google Scholar 

  64. Tlsty, T. D., Margolin, B. H., and Lum, K. Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbruck fluctuation analysis. Proc. Natl. Acad. Sci. USA 86:9441–9445, 1989.

    Article  CAS  PubMed  Google Scholar 

  65. Eshleman, J. R. and Markowitz, S. D. Mismatch repair defects in human carcinogenesis. Hum. Mol. Genet. 5:1489–1494, 1996.

    CAS  PubMed  Google Scholar 

  66. Lengauer, C., Kinzler, K. W., and Vogelstein, B. Genetic instability in colorectal cancers. Nature 386:623–627, 1997.

    Article  CAS  PubMed  Google Scholar 

  67. Cahill, D. P., Lengauer, C., Yu, J., et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392:300–303, 1998.

    Article  CAS  PubMed  Google Scholar 

  68. Greenblatt, M. S., Bennett, W. P., Hollstein, M., and Harris, C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54:4855–4878, 1994.

    CAS  PubMed  Google Scholar 

  69. Baker, S. J., Fearon, E. R., Nigro, J. M., et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221, 1989.

    Article  CAS  PubMed  Google Scholar 

  70. Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49:4682–4689, 1989.

    CAS  PubMed  Google Scholar 

  71. Dalla-Favera, R., Martinotti, S., Gallo, R. C., Erikson, J., and Croce, C. M. Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 219:963–967, 1983.

    Article  CAS  PubMed  Google Scholar 

  72. Coleman, W. B. and Tsongalis, G. J. The role of genomic instability in the development of human cancer, in The Molecular Basis of Human Cancer, Coleman, W. B. and Tsongalis, G. J., eds., Humana Pr, Totowa, NJ, 2002, pp. 115–142.

    Google Scholar 

  73. Rosenberg, S. M., Thulin, C., and Harris, R. S. Transient and heritable mutators in adaptive evolution in the lab and in nature. Genetics 148:1559–1566, 1998.

    CAS  PubMed  Google Scholar 

  74. Aaltonen, L. A., Peltomaki, P., Leach, F. S., et al. Clues to the patho-genesis of familial colorectal cancer. Science 260:812–816, 1993.

    Article  CAS  PubMed  Google Scholar 

  75. Aaltonen, L. A., Peltomaki, P., Mecklin, J. P., et al. Replication errors in benign and malignant tumors from hereditary nonpolypo-sis colorectal cancer patients. Cancer Res. 54:1645–1648, 1994.

    CAS  PubMed  Google Scholar 

  76. Akiyama, Y., Iwanaga, R., Saitoh, K., et al. Transforming growth factor beta type II receptor gene mutations in adenomas from hereditary nonpolyposis colorectal cancer. Gastroenterology 112:33–39, 1997.

    Article  CAS  PubMed  Google Scholar 

  77. Feig, D. I., Reid, T. M., and Loeb, L. A. Reactive oxygen species in tumorigenesis. Cancer Res. 54:1890s–1894s, 1994.

    CAS  PubMed  Google Scholar 

  78. Jackson, A. L., Chen, R., and Loeb, L. A. Induction of microsatellite instability by oxidative DNA damage. Proc. Natl. Acad. Sci. USA 95:12,468–12,473, 1998.

    CAS  Google Scholar 

  79. Baba, S. Recent advances in molecular genetics of colorectal cancer. World J. Surg. 21:678–687, 1997.

    Article  CAS  PubMed  Google Scholar 

  80. Yamada, N. A., Parker, J. M., and Farber, R. A. Mutation frequency analysis of mononucleotide and dinucleotide repeats after oxidative stress. Environ. Mol. Mutagen. 42:75–84, 2003.

    Article  CAS  PubMed  Google Scholar 

  81. Sarasin, A. An overview of the mechanisms of mutagenesis and car-cinogenesis. Mutat. Res. 544:99–106, 2003.

    Article  CAS  PubMed  Google Scholar 

  82. Kastan, M. B. and Kuerbitz, S. J. Control of G1 arrest after DNA damage. Environ. Health Perspect. 101(Suppl. 5):55–58, 1993.

    Article  CAS  PubMed  Google Scholar 

  83. Coleman, W. B. and Tsongalis, G. J. Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation. Clin. Chem. 41:644–657, 1995.

    CAS  PubMed  Google Scholar 

  84. Marti, T. M. and Fleck, O. DNA repair nucleases. Cell. Mol. Life Sci 61:336–354, 2004.

    Article  CAS  PubMed  Google Scholar 

  85. Bootsma, D., Kraemer, K. H., Cleaver, J. E., and Hoeijmakers, J. H. J. Nucleotide excision repair syndromes: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, in The Metabolic and Molecular Basis of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Va lle, D., eds., McGraw-Hill, New York, 2001, pp. 677–704.

    Google Scholar 

  86. Gatti, R. A. Ataxia–telangiectasia, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 705–732.

    Google Scholar 

  87. Swift, M., Morrell, D., Massey, R. B., and Chase, C. L. Incidence of cancer in 161 families affected by ataxia–telangiectasia. N. Engl. J. Med. 325:1831–1836, 1991.

    Article  CAS  PubMed  Google Scholar 

  88. Thorstenson, Y. R., Roxas, A., Kroiss, R., et al. Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 63:3325–3333, 2003.

    CAS  PubMed  Google Scholar 

  89. Auerbach, A. D., Buchwald, M., and Joenje, H. Fanconi anemia, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 753–768.

    Google Scholar 

  90. Bagby, G. C., Jr. Genetic basis of Fanconi anemia. Curr. Opin. Hematol. 10:68–76, 2003.

    Article  CAS  PubMed  Google Scholar 

  91. German, J. Bloom ’s syndrome. XX. The first 100 cancers. Cancer Genet. Cytogenet. 93:100–106, 1997.

    Article  CAS  PubMed  Google Scholar 

  92. German, J. and Ellis, N. A. Bloom syndrome, in The Metabolic and Molecular Basis of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 733–752.

    Google Scholar 

  93. Langlois, R. G., Bigbee, W. L., Jensen, R. H., and German, J. Evidence for increased in vivo mutation and somatic recombination in Bloom ’s syndrome. Proc. Natl. Acad. Sci. USA 86:670–674, 1989.

    Article  CAS  PubMed  Google Scholar 

  94. Norgauer, J., Idzko, M., Panther, E., Hellstern, O., and Herouy, Y. Xeroderma pigmentosum. Eur. J. Dermatol. 13:4–9, 2003.

    PubMed  Google Scholar 

  95. Gatti, R. A. Localizing the genes for ataxia-telangiectasia: a human model for inherited cancer susceptibility. Adv. Cancer Res. 56:77–104, 1991.

    Article  CAS  PubMed  Google Scholar 

  96. Digweed, M. Human genetic instability syndromes: single gene defects with increased risk of cancer. Toxicol. Lett. 67:259–281, 1993.

    Article  CAS  PubMed  Google Scholar 

  97. Groden, J., and German, J. Bloom ’s syndrome. XVIII. Hypermutability at a tandem-repeat locus. Hum. Genet. 90:360–367, 1992.

    Article  CAS  PubMed  Google Scholar 

  98. Ellis, N. A., Groden, J., Ye, T. Z., et al. The Bloom ’s syndrome gene product is homologous to RecQ helicases. Cell 83:655–666, 1995.

    Article  CAS  PubMed  Google Scholar 

  99. Cleaver, J. E., and Kraemer, K. H. Xeroderma pigmentosum and Cockayne syndrome, in The Metabolic and Molecualr Bases of Inherited Disease, 7th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 1995, pp. 4393–4419.

    Google Scholar 

  100. Savitsky, K., Bar-Shira, A., Gilad, S., et al. A single ataxia telang-iectasia gene with a product similar to PI-3 kinase. Science 268:1749–1753, 1995.

    Article  CAS  PubMed  Google Scholar 

  101. Shiloh, Y. AT M and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3:155–168, 2003.

    Article  CAS  PubMed  Google Scholar 

  102. Mitelman, F. Catalog of Chromosome Aberrations in Cancer, 5th ed, Wiley–Liss, New York, 1994.

    Google Scholar 

  103. Meltzer, P. S., Kallioniemi, A., and Trent, J. M. Chromosome alterations in human solid tumors, in The Metabolic and Molecular Bases of Inhierited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 575–596.

    Google Scholar 

  104. Cahill, D. P. and Lengauer, C. Tumor genome instabilities, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 611–612.

    Google Scholar 

  105. Wang, Z., Cummins, J. M., Shen, D., et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res. 64:2998–3001, 2004.

    Article  CAS  PubMed  Google Scholar 

  106. Vogelstein, B., Fearon, E. R., Kern, S. E., et al. Allelotype of col-orectal carcinomas. Science 244:207–211,1989.

    Article  CAS  PubMed  Google Scholar 

  107. Tsuchiya, E., Nakamura, Y., Weng, S. Y., et al. Allelotype of non-small cell lung carcinomac —omparison between loss of heterozy-gosity in squamous cell carcinoma and adenocarcinoma. Cancer Res. 52:2478–2481, 1992.

    CAS  PubMed  Google Scholar 

  108. Seymour, A. B., Hruban, R. H., Redston, M., et al. Allelotype of pancreatic adenocarcinoma. Cancer Res. 54:2761–2764, 1994.

    CAS  PubMed  Google Scholar 

  109. Roncalli, M., Borzio, M., Bianchi, P., and Laghi, L. Comprehensive allelotype study of hepatocellular carcinoma. Hepatology 32:876, 2000.

    Article  CAS  PubMed  Google Scholar 

  110. Miller, B. J., Wang, D., Krahe, R., and Wright, F. A. Pooled analysis of loss of heterozygosity in breast cancer: a genome scan provides comparative evidence for multiple tumor suppressors and identifies novel candidate regions. Am. J. Hum. Genet. 73:748–767, 2003.

    Article  CAS  PubMed  Google Scholar 

  111. Thiagalingam, S., Laken, S., Willson, J. K., et al. Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc. Natl. Acad. Sci. USA 98:2698–2702, 2001.

    Article  CAS  PubMed  Google Scholar 

  112. El-Naggar, A. K. and Vielh, P. Solid tumor DNA content analysis. Methods Mol. Biol. 263:355–370, 2004.

    CAS  PubMed  Google Scholar 

  113. Kallioniemi, O. P., Kallioniemi, A., Piper, J., et al. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 10:231–243, 1994.

    Article  CAS  PubMed  Google Scholar 

  114. Kallioniemi, O. P., Kallioniemi, A., Sudar, D., et al. Comparative genomic hybridization: a rapid new method for detecting and mapping DNA amplification in tumors. Semin. Cancer Biol. 4:41–46, 1993.

    CAS  PubMed  Google Scholar 

  115. Bayani, J. M. and Squire, J. A. Applications of SKY in cancer cyto-genetics. Cancer Invest. 20:373–386, 2002.

    Article  PubMed  Google Scholar 

  116. Kakazu, N., Bar-Am, I., Hada, S., Ago, H., and Abe, T. A new chromosome banding technique, spectral color banding (SCAN), for full characterization of chromosomal abnormalities. Genes Chromosomes Cancer 37:412–416, 2003.

    Article  CAS  PubMed  Google Scholar 

  117. Solomon, E., Borrow, J., and Goddard, A. D. Chromosome aberrations and cancer. Science 254:1153–1160, 1991.

    Article  CAS  PubMed  Google Scholar 

  118. Patel, A. S., Hawkins, A. L., and Griffin, C. A. Cytogenetics and cancer. Curr. O pin. Oncol. 12:62–67, 2000.

    Article  CAS  Google Scholar 

  119. Radford, D. M., Fair, K. L., Phillips, N. J., et al. Allelotyping of duc-tal carcinoma in situ of the breast: deletion of loci on 8p, 13q, 16q, 17p and 17q. Cancer Res. 55:3399–3405, 1995.

    CAS  PubMed  Google Scholar 

  120. Boige, V., Laurent-Puig, P., Fouchet, P., et al. Concerted nonsyn-tenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype. Cancer Res. 57:1986–1990, 1997.

    CAS  PubMed  Google Scholar 

  121. Nowak, M. A., Komarova, N. L., Sengupta, A., et al. The role of chromosomal instability in tumor initiation. Proc. Natl. Acad. Sci. USA 99:16,226–16,231, 2002.

    Article  CAS  Google Scholar 

  122. Rajagopalan, H., Nowak, M. A., Vogelstein, B., and Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nat. Rev. Cancer 3:695–701, 2003.

    Article  CAS  PubMed  Google Scholar 

  123. Ghadimi, B. M., Sackett, D. L., Difilippantonio, M. J., et al. Centrosome amplification and instability occurs exclusively in ane-uploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosomes Cancer 27:183–190, 2000.

    Article  CAS  PubMed  Google Scholar 

  124. Harwood, J., Tachibana, A., Davis, R., Bhattacharyya, N. P., and Meuth, M. High rate of multilocus deletion in a human tumor cell line. Hum. Mol. Genet. 2:165–171, 1993.

    Article  CAS  PubMed  Google Scholar 

  125. Phear, G., Bhattacharyya, N. P., and Meuth, M. Loss of heterozy-gosity and base substitution at the APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. Mol. Cell. Biol. 16:6516–6523, 1996.

    CAS  PubMed  Google Scholar 

  126. Le Beau, M. M. Molecular biology of cancer: cytogenetics, in Cancer: Principles and Practice of Oncology, 5th ed., DeVita, V. T., Hellman, S., and Rosenberg, S. A., eds., Lippincott–Raven, Philadelphia, PA, pp. 103–119.

    Google Scholar 

  127. Gollin, S. M. Chromosomal instability. Curr. O pin. Oncol. 16: 25–31, 2004.

    Article  Google Scholar 

  128. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51:6304–6311, 1991.

    CAS  PubMed  Google Scholar 

  129. Jong, Y. J., Li, L. H., Tsou, M. H., et al. Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human breast cancers: correlation with disease progression and TP53 mutations. Cancer Genet. Cytogenet. 148:55–65, 2004.

    Article  CAS  PubMed  Google Scholar 

  130. Sugai, T., Takahashi, H., Habano, W., et al. Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas. J. Pathol. 200:168–176, 2003.

    Article  CAS  PubMed  Google Scholar 

  131. Filatov, L., Golubovskaya, V., Hurt, J. C., Byrd, L. L., Phillips, J. M., and Kaufmann, W. K. Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein. Oncogene 16:1825–1838, 1998.

    Article  CAS  PubMed  Google Scholar 

  132. Honma, M., Momose, M., Tanabe, H., et al. Requirement of wildtype p53 protein for maintenance of chromosomal integrity. Mol. Carcinog. 28:203–214, 2000.

    Article  CAS  PubMed  Google Scholar 

  133. Tarapore, P. and Fukasawa, K. p53 mutation and mitotic infidelity. Cancer Invest. 18:148–155, 2000.

    Article  CAS  PubMed  Google Scholar 

  134. Shih, I. M., Zhou, W., Goodman, S. N., Lengauer, C., Kinzler, K. W., and Vogelstein, B. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 61:818–822, 2001.

    CAS  PubMed  Google Scholar 

  135. Baker, S. J., Preisinger, A. C., Jessup, J. M., et al. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 50:7717–7722, 1990.

    CAS  PubMed  Google Scholar 

  136. Eshleman, J. R., Casey, G., Kochera, M. E., et al. Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene 17:719–725, 1998.

    Article  CAS  PubMed  Google Scholar 

  137. Kramer, A., Neben, K., and Ho, A. D. Centrosome replication, genomic instability and cancer. Leukemia 16:767–775, 2002.

    Article  CAS  PubMed  Google Scholar 

  138. Lingle, W. L., Barrett, S. L., Negron, V. C., et al. Centrosome amplification drives chromosomal instability in breast tumor development. Proc. Natl. Acad. Sci. USA 99:1978–1983, 2002.

    Article  CAS  PubMed  Google Scholar 

  139. Bischoff, J. R., Anderson, L., Zhu, Y., et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human col-orectal cancers. EMBO J. 17:3052–3065.

    Google Scholar 

  140. Zhou, H., Kuang, J., Zhong, L., et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat. Genet. 20:189–193, 1998.

    Article  CAS  PubMed  Google Scholar 

  141. Wolf, G., Elez, R., Doermer, A., et al. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 14:543–549, 1997.

    Article  CAS  PubMed  Google Scholar 

  142. Tanaka, T., Kimura, M., Matsunaga, K., Fukada, D., Mori, H., and Okano, Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res. 59:2041–2044, 1999.

    CAS  PubMed  Google Scholar 

  143. Carroll, P. E., Okuda, M., Horn, H. F., et al. Centrosome hyperam-plification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 18:1935–1944, 1999.

    Article  CAS  PubMed  Google Scholar 

  144. Tarapore, P. and Fukasawa, K. Loss of p53 and centrosome hyper-amplification. Oncogene 21:6234–6240, 2002.

    Article  CAS  PubMed  Google Scholar 

  145. Tutt, A., Gabriel, A., Bertwistle, D., et al. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr. Biol. 9:1107–1110, 1999.

    Article  CAS  PubMed  Google Scholar 

  146. Deng, C. X. Roles of BRCA1 in centrosome duplication. Oncogene 21:6222–6227, 2002.

    Article  CAS  PubMed  Google Scholar 

  147. Bharadwaj, R. and Yu, H. The spindle checkpoint, aneuploidy, and cancer. Oncogene 23:2016–2027, 2004.

    Article  CAS  PubMed  Google Scholar 

  148. Hartwell, L. H. and Kastan, M. B. Cell cycle control and cancer. Science 266:1821–1828, 1994.

    Article  CAS  PubMed  Google Scholar 

  149. Cahill, D. P., da Costa, L. T., Carson-Walter, E. B., Kinzler, K. W., Vogelstein, B., and Lengauer, C. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58:181–187, 1999.

    Article  CAS  PubMed  Google Scholar 

  150. Li, Y. and Benezra, R. Identification of a human mitotic checkpoint gene: hsMAD2. Science 274:246–248, 1996.

    Article  CAS  PubMed  Google Scholar 

  151. Jaffrey, R. G., Pritchard, S. C., Clark, C., et al. Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer. Cancer Res. 60:4349–4352, 2000.

    CAS  PubMed  Google Scholar 

  152. Myrie, K. A., Percy, M. J., Azim, J. N., Neeley, C. K., and Petty, E. M. Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Cancer Lett. 152:193–199, 2000.

    Article  CAS  PubMed  Google Scholar 

  153. Sato, M., Sekido, Y., Horio, Y., et al. Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer. Jpn. J. Cancer Res. 91:504–509, 2000.

    CAS  PubMed  Google Scholar 

  154. Yamaguchi, K., Okami, K., Hibi, K., Wehage, S. L., Jen, J., and Sidransky, D. Mutation analysis of hBUB1 in aneuploid HNSCC and lung cancer cell lines. Cancer Lett. 139:183–187, 1999.

    Article  CAS  PubMed  Google Scholar 

  155. Imai,Y., Shiratori, Y., Kato, N., Inoue, T., and Omata, M. Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Jpn. J. Cancer Res. 90:837–840, 1999.

    CAS  PubMed  Google Scholar 

  156. Gualberto, A., Aldape, K., Kozakiewicz, K., and Tlsty, T. D. An oncogenic form of p53 confers a dominant, gain-of-function pheno-type that disrupts spindle checkpoint control. Proc. Natl. Acad. Sci. USA 95:5166–5171, 1998.

    Article  CAS  PubMed  Google Scholar 

  157. Shigeta, T., Takagi, M., Delia, D., et al. Defective control of apop-tosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. Cancer Res. 59:2602–2607, 1999.

    CAS  PubMed  Google Scholar 

  158. Canman, C. E. and Lim, D. S. The role of ATM in DNA damage responses and cancer. Oncogene 17:3301–3308, 1998.

    Article  PubMed  Google Scholar 

  159. Zhang, H., Tombline, G., and Weber, B. L. BRCA1, BRCA2, and DNA damage response: collision or collusion? Cell 92:433–436, 1998.

    Article  CAS  PubMed  Google Scholar 

  160. Tlsty, T. D., Briot, A., Gualberto, A., et al. Genomic instability and cancer. Mutat. Res. 337:1–7, 1995.

    CAS  PubMed  Google Scholar 

  161. Hogarty, M. D. and Brodeur, G. M. Gene amplification in human cancers: biological and clinical significance, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 597–610.

    Google Scholar 

  162. Livingstone, L. R., White, A., Sprouse, J., Livanos, E., Jacks, T., and Tlsty, T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70:923–935, 1992.

    Article  CAS  PubMed  Google Scholar 

  163. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C., and Wahl, G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70:937–948, 1992.

    Article  CAS  PubMed  Google Scholar 

  164. Oren, M. Relationship of p53 to the control of apoptotic cell death. Semin. Cancer Biol. 5:221–227, 1994.

    CAS  PubMed  Google Scholar 

  165. Dubeau, L. Ovarian cancer, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 1091–1096.

    Google Scholar 

  166. Hruban, R. H., Wilentz, R. E., and Kern, S. E. Genetic progression in the pancreatic ducts. Am. J. Pathol. 156:1821–1825, 2000.

    CAS  PubMed  Google Scholar 

  167. Croce, C. M. Chromosome translocations and human cancer. Cancer Res. 46:6019–6023, 1986.

    CAS  PubMed  Google Scholar 

  168. Groden, J., Thliveris, A., Samowitz, W., et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600, 1991.

    Article  CAS  PubMed  Google Scholar 

  169. Kinzler, K. W., Nilbert, M. C., Su, L. K., et al. Identification of FAP locus genes from chromosome 5q21. Science 253:661–665, 1991.

    Article  CAS  PubMed  Google Scholar 

  170. Kinzler, K. W., Nilbert, M. C., Vogelstein, B., et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251:1366–1370, 1991.

    Article  CAS  PubMed  Google Scholar 

  171. Nishisho, I., Nakamura, Y., Miyoshi, Y., et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669, 1991.

    Article  CAS  PubMed  Google Scholar 

  172. Fearon, E. R., Cho, K. R., Nigro, J. M., et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247:49–56, 1990.

    Article  CAS  PubMed  Google Scholar 

  173. Sutherland, G. R. and Richards, R. I. Simple tandem DNA repeats and human genetic disease. Proc. Natl. Acad. Sci. USA 92:3636–3641, 1995.

    Article  CAS  PubMed  Google Scholar 

  174. Peinado, M. A., Malkhosyan, S., Velazquez, A., and Perucho, M. Isolation and characterization of allelic losses and gains in colorec-tal tumors by arbitrarily primed polymerase chain reaction. Proc. Natl. Acad. Sci. USA 89:10,065–10,069, 1992.

    Article  CAS  Google Scholar 

  175. Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D., and Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561, 1993.

    Article  CAS  PubMed  Google Scholar 

  176. Thibodeau, S. N., Bren, G., and Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260:816–819, 1993.

    Article  CAS  PubMed  Google Scholar 

  177. Zhang, L., Yu, J., Willson, J. K., Markowitz, S. D., Kinzler, K. W., and Vogelstein, B. Short mononucleotide repeat sequence variability in mismatch repair-deficient cancers. Cancer Res. 61:3801–3805, 2001.

    CAS  PubMed  Google Scholar 

  178. Dietmaier, W., Wallinger, S., Bocker, T., Kullmann, F., Fishel, R., and Ruschoff, J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 57:4749–4756, 1997.

    CAS  PubMed  Google Scholar 

  179. Thibodeau, S. N., French, A. J., Cunningham, J. M., et al. Microsatellite instability in colorectal cancer: different mutator phe-notypes and the principal involvement of hMLH1. Cancer Res. 58:1713–1718, 1998.

    CAS  PubMed  Google Scholar 

  180. Frazier, M. L., Sinicrope, F. A., Amos, C. I., et al. Loci for efficient detection of microsatellite instability in hereditary non-polyposis colorectal cancer. Oncol. Rep. 6:497–505, 1999.

    CAS  PubMed  Google Scholar 

  181. Yamada, N. A., Castro, A., and Farber, R. A. Variation in the extent of microsatellite instability in human cell lines with defects in different mismatch repair genes. Mutagenesis 18:277–282, 2003.

    Article  CAS  PubMed  Google Scholar 

  182. Honchel, R., Halling, K. C., and Thibodeau, S. N. Genomic instability in neoplasia. Semin. Cell. Biol. 6:45–52, 1995.

    Article  CAS  PubMed  Google Scholar 

  183. Peltomaki, P. DNA mismatch repair gene mutations in human cancer. Environ. Health Perspect. 105 (Suppl. 4):775–780, 1997.

    Article  CAS  PubMed  Google Scholar 

  184. Hoang, J. M., Cottu, P. H., Thuille, B., Salmon, R. J., Thomas, G., and Hamelin, R. BAT-26, an indicator of the replication error phe-notype in colorectal cancers and cell lines. Cancer Res. 57:300–303, 1997.

    CAS  PubMed  Google Scholar 

  185. Zhou, X. P., Hoang, J. M., Li, Y. J., et al. Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer 21:101–107, 1998.

    Article  CAS  PubMed  Google Scholar 

  186. Parsons, R., Myeroff, L. L., Liu, B., et al. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 55:5548–5550, 1995.

    CAS  PubMed  Google Scholar 

  187. Parsons, R., Li, G. M., Longley, M. J., et al. Hypermutability and mismatch repair deficiency in RER + tumor cells. Cell 75:1227–1236, 1993.

    Article  CAS  PubMed  Google Scholar 

  188. Chen, J., Heerdt, B. G., and Augenlicht, L. H. Presence and instability of repetitive elements in sequences the altered expression of which characterizes risk for colonic cancer. Cancer Res. 55:174–180, 1995.

    CAS  PubMed  Google Scholar 

  189. Eichler, E. E., Holden, J. J., Popovich, B. W., et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat. Genet. 8:88–94, 1994.

    Article  CAS  PubMed  Google Scholar 

  190. Mao, L., Lee, D. J., Tockman, M. S., Erozan, Y. S., Askin, F., and Sidransky, D. Microsatellite alterations as clonal markers for the detection of human cancer. Proc. Natl. Acad. Sci. USA 91:9871–9875, 1994.

    Article  CAS  PubMed  Google Scholar 

  191. Risinger, J. I., Umar, A., Barrett, J. C., and Kunkel, T. A. A hPMS2 mutant cell line is defective in strand-specific mismatch repair. J. Biol. Chem. 270:18, 183–18,186, 1995.

    CAS  Google Scholar 

  192. Risinger, J. I., Umar, A., Boyd, J., Berchuck, A., Kunkel, T. A., and Barrett, J. C. Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nat. Genet. 14:102–105, 1996.

    Article  CAS  PubMed  Google Scholar 

  193. Oki, E., Oda, S., Maehara, Y., and Sugimachi, K. Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorec-tal carcinoma cell lines deficient in DNA mismatch repair. Oncogene 18:2143–2147, 1999.

    Article  CAS  PubMed  Google Scholar 

  194. Bennett, S. E., Umar, A., Oshima, J., Monnat, R. J., Jr., and Kunkel, T. A. Mismatch repair in extracts of Werner syndrome cell lines. Cancer Res. 57:2956–2960, 1997.

    CAS  PubMed  Google Scholar 

  195. Li, G. M. and Modrich, P. Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc. Natl. Acad. Sci. USA 92:1950–1954, 1995.

    Article  CAS  PubMed  Google Scholar 

  196. Papadopoulos, N., Nicolaides, N. C., Wei, Y. F., et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263:1625–1629, 1994.

    Article  CAS  PubMed  Google Scholar 

  197. Glaab, W. E., Risinger, J. I., Umar, A., Kunkel, T. A., Barrett, J. C., and Tindall, K. R. Characterization of distinct human endometrial carcinoma cell lines deficient in mismatch repair that originated from a single tumor. J. Biol. Chem. 273:26,662–26,669, 1998.

    Article  CAS  Google Scholar 

  198. Baranovskaya, S., Soto, J. L., Perucho, M., and Malkhosyan, S. R. Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype. Proc. Natl. Acad. Sci. USA 98:15107–15,112, 2001.

    Article  CAS  PubMed  Google Scholar 

  199. Bocker, T., Diermann, J., Friedl, W., et al. Microsatellite instability analysis: a multicenter study for reliability and quality control. Cancer Res. 57:4739–4743, 1997.

    CAS  PubMed  Google Scholar 

  200. Boland, C. R., Thibodeau, S. N., Hamilton, S. R., et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorec-tal cancer. Cancer Res. 58:5248–5257, 1998.

    CAS  PubMed  Google Scholar 

  201. Siah, S. P., Quinn, D. M., Bennett, G. D., et al. Microsatellite instability markers in breast cancer: a review and study showing MSI was not detected at “BAT 25 ” and “BAT 26 ” microsatellite markers in early-onset breast cancer. Breast Cancer Res. Treat. 60:135–142, 2000.

    Article  CAS  PubMed  Google Scholar 

  202. Luqmani, Y. A. and Mathew, M., Allelic variation of BAT-25 and BAT-26 mononucleotide repeat loci in tumours from a group of young women with breast cancer. Int. J. Oncol. 25:771–775, 2004.

    CAS  PubMed  Google Scholar 

  203. Fujiwara, T., Stolker, J. M., Watanabe, T., et al. Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am. J. Pathol. 153:1063–1078, 1998.

    CAS  PubMed  Google Scholar 

  204. Bocker, T., Schlegel, J., Kullmann, F., et al. Genomic instability in colorectal carcinomas: comparison of different evaluation methods and their biological significance. J. Pathol. 179:15–19, 1996.

    Article  CAS  PubMed  Google Scholar 

  205. Sood, A. K., Holmes, R., Hendrix, M. J., and Buller, R. E. Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer. Cancer Res. 61:4371–4371, 2001.

    CAS  PubMed  Google Scholar 

  206. Horii, A., Han, H. J., Shimada, M., et al. Frequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers. Cancer Res. 54:3373–3375, 1994.

    CAS  PubMed  Google Scholar 

  207. Akiyama, Y., Nakasaki, H., Nihei, Z., et al. Frequent microsatellite instabilities and analyses of the related genes in familial gastric cancers. Jpn. J. Cancer Res. 87:595–601, 1996.

    CAS  PubMed  Google Scholar 

  208. Nakashima, H., Honda, M., Inoue, H., et al. Microsatellite instability in multiple gastric cancers. Int. J. Cancer 64:239–242, 1995.

    Article  CAS  PubMed  Google Scholar 

  209. Contegiacomo, A., Palmirotta, R., De Marchis, L., et al. Microsatellite instability and pathological aspects of breast cancer. Int. J. Cancer 64:264–268, 1995.

    Article  CAS  PubMed  Google Scholar 

  210. Paulson, T. G., Wright, F. A., Parker, B. A., Russack, V., and W a hl, G. M. Microsatellite instability correlates with reduced survival and poor disease prognosis in breast cancer. Cancer Res. 56:4021–4026, 1996.

    CAS  PubMed  Google Scholar 

  211. De Marchis, L., Contegiacomo, A., D ’Amico, C., et al. Microsatellite instability is correlated with lymph node-positive breast cancer. Clin. Cancer Res. 3:241–248, 1997.

    PubMed  Google Scholar 

  212. Caldes, T., Perez-Segura, P., Tosar, A., de La Hoya, M., and Diaz-Rubio, E. Microsatellite instability correlates with negative expression of estrogen and progesterone receptors in sporadic breast cancer. Teratog. Carcinog. Mutagen. 20:283–291, 2000.

    Article  CAS  PubMed  Google Scholar 

  213. Imyanitov, E. N., Togo, A. V., Suspitsin, E. N., et al. Evidence for microsatellite instability in bilateral breast carcinomas. Cancer Lett. 154:9–17, 2000.

    Article  CAS  PubMed  Google Scholar 

  214. Richard, S. M., Bailliet, G., Paez, G. L., Bianchi, M. S., Peltomaki, P., and Bianchi, N. O. Nuclear and mitochondrial genome instability in human breast cancer. Cancer Res. 60:4231–4237, 2000.

    CAS  PubMed  Google Scholar 

  215. Jiricny, J., and Nystrom-Lahti, M. Mismatch repair defects in cancer. Curr. Opin. Genet. Dev. 10:157–161, 2000.

    Article  CAS  PubMed  Google Scholar 

  216. Fishel, R., Lescoe, M. K., Rao, M. R., et al. The human mutator gene homolog MSH2 and its association with hereditary nonpoly-posis colon cancer. Cell. 75:1027–1038, 1993.

    Article  CAS  PubMed  Google Scholar 

  217. Leach, F. S., Nicolaides, N. C., Papadopoulos, N., et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225, 1993.

    Article  CAS  PubMed  Google Scholar 

  218. Umar, A., Risinger, J. I., Glaab, W. E., Tindall, K. R., Barrett, J. C., and Kunkel, T. A. Functional overlap in mismatch repair by human MSH3 and MSH6. Genetics 148:1637–1646, 1998.

    CAS  PubMed  Google Scholar 

  219. Palombo, F., Gallinari, P., Iaccarino, I., et al GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268:1912–1914, 1995.

    Article  CAS  PubMed  Google Scholar 

  220. Papadopoulos, N., Nicolaides, N. C., Liu, B., et al. Mutations of GTBP in genetically unstable cells. Science 268:1915–1917, 1995.

    Article  CAS  PubMed  Google Scholar 

  221. Bronner, C. E., Baker, S. M., Morrison, P. T., et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261, 1994.

    Article  CAS  PubMed  Google Scholar 

  222. Nicolaides, N. C., Papadopoulos, N., Liu, B., et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80, 1994.

    Article  CAS  PubMed  Google Scholar 

  223. Lipkin, S. M., Wang, V., Jacoby, R., et al. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat. Genet. 24:27–35, 2000.

    Article  CAS  PubMed  Google Scholar 

  224. Bapat, B. V., Madlensky, L., Temple, L. K., et al. Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer. Hum. Genet. 104:167–176, 1999.

    Article  CAS  PubMed  Google Scholar 

  225. Loukola, A., Vilkki, S., Singh, J., Launonen, V., and Aaltonen, L. A. Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. Am. J. Pathol. 157:347–152, 2000.

    CAS  PubMed  Google Scholar 

  226. Planck, M., Wenngren, E., Borg, A., Olsson, H., and Nilbert, M. Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation. Genes Chromosomes Cancer 29:33–39, 2000.

    Article  CAS  PubMed  Google Scholar 

  227. Muller, A. and Fishel, R. Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest. 20:102–109, 2002.

    Article  PubMed  Google Scholar 

  228. Liu, B., Nicolaides, N. C., Markowitz, S., et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat. Genet 9:48–55, 1995.

    Article  CAS  PubMed  Google Scholar 

  229. Moslein, G., Tester, D. J., Lindor, N. M., et al. Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. Hum. Mol. Genet. 5:1245–1252, 1996.

    Article  CAS  PubMed  Google Scholar 

  230. Schmutte, C. and Fishel, R. Genomic instability: first step to car-cinogenesis. Anticancer Res. 19:4665–4696, 1999.

    CAS  PubMed  Google Scholar 

  231. Arzimanoglou, II, Gilbert, F., and Barber, H. R. Microsatellite instability in human solid tumors. Cancer 82:1808–1820, 1998.

    Article  CAS  PubMed  Google Scholar 

  232. Lothe, R. A. Microsatellite instability in human solid tumors. Mol. Med. Today 3:61–68, 1997.

    Article  CAS  PubMed  Google Scholar 

  233. Schlotterer, C. and Tautz, D. Slippage synthesis of simple sequence DNA. Nucleic Acids Res. 20:211–215, 1992.

    Article  CAS  PubMed  Google Scholar 

  234. Coleman, W. B. and Tsongalis, G. J. The role of genomic instability in human carcinogenesis. Anticancer Res. 19:4645–4664, 1999.

    CAS  PubMed  Google Scholar 

  235. Thomas, D. C., Umar, A., and Kunkel, T. A. Microsatellite instability and mismatch repair defects in cancer. Mutat. Res. 350:201–205, 1996.

    PubMed  Google Scholar 

  236. Lovett, S. T. and Feschenko, V. V. Stabilization of diverged tandem repeats by mismatch repair: evidence for deletion formation via a misaligned replication intermediate. Proc. Natl. Acad. Sci. USA 93:7120–7124, 1996.

    Article  CAS  PubMed  Google Scholar 

  237. Boyer, J. C. and Farber, R. A. Mutation rate of a microsatellite sequence in normal human fibroblasts. Cancer Res. 58:3946–3949, 1998.

    CAS  PubMed  Google Scholar 

  238. Hanford, M. G., Rushton, B. C., Gowen, L. C., and Farber, R. A. Microsatellite mutation rates in cancer cell lines deficient or proficient in mismatch repair. Oncogene 16:2389–2393, 1998.

    Article  CAS  PubMed  Google Scholar 

  239. Umar, A., Koi, M., Risinger, J. I., et al. Correction of hypermutability, N-methyl-N ’-nitro-N-nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. Cancer Res. 57:3949–3955, 1997.

    CAS  PubMed  Google Scholar 

  240. da Costa, L. T., Liu, B., el-Deiry, W., et al. Polymerase delta variants in RER colorectal tumours. Nat. Genet. 9:10–11, 1995.

    Article  PubMed  Google Scholar 

  241. Parc, Y. R., Halling, K. C., Wang, L., et al. HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res. 60:2225–2231, 2000.

    CAS  PubMed  Google Scholar 

  242. Verma, L., Kane, M. F., Brassett, C., et al. Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. J. Med. Genet. 36:678–682, 1999.

    CAS  PubMed  Google Scholar 

  243. Koi, M., Umar, A., Chauhan, D. P., et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N ’-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 54:4308–4312, 1994.

    CAS  PubMed  Google Scholar 

  244. Risinger, J. I., Umar, A., Glaab, W. E., Tindall, K. R., Kunkel, T. A., and Barrett, J. C. Single gene complementation of the hPMS2 defect in HEC-1-A endometrial carcinoma cells. Cancer Res. 58:2978–2981, 1998.

    CAS  PubMed  Google Scholar 

  245. Lettieri, T., Marra, G., Aquilina, G., et al. Effect of hMSH6 cDNA expression on the phenotype of mismatch repair-deficient colon cancer cell line HCT15. Carcinogenesis 20, 373–382, 1999.

    Article  CAS  PubMed  Google Scholar 

  246. Ahuja, N., Mohan, A. L., Li, Q., et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 57:3370–3374, 1997.

    CAS  PubMed  Google Scholar 

  247. Lengauer, C., Kinzler, K. W., and Vogelstein, B. DNA methylation and genetic instability in colorectal cancer cells. Proc. Natl. Acad. Sci. USA 94:2545–2550, 1997.

    Article  CAS  PubMed  Google Scholar 

  248. Cunningham, J. M., Christensen, E. R., Tester, D. J., et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58:3455–3460, 1998.

    CAS  PubMed  Google Scholar 

  249. Herman, J. G., Umar, A., Polyak, K., et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA 95:6870–6875, 1995.

    Article  Google Scholar 

  250. Kane, M. F., Loda, M., Gaida, G. M., et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57:808–811, 1997.

    CAS  PubMed  Google Scholar 

  251. Bevilacqua, R. A. and Simpson, A. J. Methylation of the hMLH1 promoter but no hMLH1 mutations in sporadic gastric carcinomas with high-level microsatellite instability. Int. J. Cancer 87:200–203, 2000.

    Article  CAS  PubMed  Google Scholar 

  252. Endoh, Y., Tamura, G., Ajioka, Y., Watanabe, H., and Motoyama, T. Frequent hypermethylation of the hMLH1 gene promoter in differ-entiated-type tumors of the stomach with the gastric foveolar phe-notype. Am. J. Pathol. 157:717–722, 2000.

    CAS  PubMed  Google Scholar 

  253. Simpkins, S. B., Bocker, T., Swisher, E. M., et al. MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum. Mol. Genet. 8:661–666, 1999.

    Article  CAS  PubMed  Google Scholar 

  254. Glaab, W. E., Hill, R. B., and Skopek, T. R. Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxi-dant ascorbate in mismatch repair-deficient human colon cancer cells. Carcinogenesis 22:1709–1713, 2001.

    Article  CAS  PubMed  Google Scholar 

  255. Ekbom, A., Helmick, C., Zack, M., and Adami, H. O. Ulcerative colitis and colorectal cancer. A population-based study. N. Engl. J. Med. 323:1228–1233, 1990.

    Article  CAS  PubMed  Google Scholar 

  256. Willenbucher, R. F., Aust, D. E., Chang, C. G., et al. Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. Am. J. Pathol. 154:1825–1830, 1999.

    CAS  PubMed  Google Scholar 

  257. Loeb, K. R. and Loeb, L. A. Genetic instability and the mutator phe-notype. Studies in ulcerative colitis. Am. J. Pathol. 154:1621–1626, 1999.

    CAS  PubMed  Google Scholar 

  258. Fleisher, A. S., Esteller, M., Tamura, G., et al. Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia. Oncogene 20:329–335, 2001.

    Article  CAS  PubMed  Google Scholar 

  259. Chang, C. L., Marra, G., Chauhan, D. P., et al. Oxidative stress inactivates the human DNA mismatch repair system. Am. J. Physiol. Cell Physiol. 283:C148–C154, 2002.

    CAS  PubMed  Google Scholar 

  260. Brentnall, T. A., Crispin, D. A., Bronner, M. P., et al. Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res. 56:1237–1240, 1996.

    CAS  PubMed  Google Scholar 

  261. Iwaya, T., Maesawa, C., Nishizuka, S., et al. Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs. Genes Chromosomes Cancer 23:317–322, 1998.

    Article  CAS  PubMed  Google Scholar 

  262. Suzuki, H., Harpaz, N., Tarmin, L., et al. Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers. Cancer Res. 54:4841–4844, 1994.

    CAS  PubMed  Google Scholar 

  263. Perucho, M. Tumors with microsatellite instability: many mutations, targets and paradoxes. Oncogene 22:2223–2225, 2003.

    Article  CAS  PubMed  Google Scholar 

  264. Duval, A. and Hamelin, R. Genetic instability in human mismatch repair deficient cancers. Ann. Genet. 45:71–75, 2002.

    PubMed  Google Scholar 

  265. Lin, H. Y., Wang, X. F., Ng-Eaton, E., Weinberg, R. A., and Lodish, H. F. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell 68:775–785, 1992.

    Article  CAS  PubMed  Google Scholar 

  266. Markowitz, S., Wang, J., Myeroff, L., et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338, 1995.

    Article  CAS  PubMed  Google Scholar 

  267. Tomita, S., Miyazato, H., Tamai, O., Muto, Y., and Toda, T. Analyses of microsatellite instability and the transforming growth factor-beta receptor type II gene mutation in sporadic human gastrointestinal cancer. Cancer Genet. Cytogenet. 115:23–27, 1999.

    Article  CAS  PubMed  Google Scholar 

  268. Leung, S. Y., Chan, T. L., Chung, L. P., et al. Microsatellite instability and mutation of DNA mismatch repair genes in gliomas. Am. J. Pathol. 153:1181–1188, 1998.

    CAS  PubMed  Google Scholar 

  269. Massague, J., Blain, S. W., and Lo, R. S. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309, 2000.

    Article  CAS  PubMed  Google Scholar 

  270. Wang, J., Sun, L., Myeroff, L., et al. Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J. Biol. Chem. 270:22,044–22,049, 1995.

    CAS  Google Scholar 

  271. Grady, W. M., Rajput, A., Myeroff, L., et al. Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 58:3101–3104, 1998.

    CAS  PubMed  Google Scholar 

  272. Woerner, S. M., Benner, A., Sutter, C., et al. Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes. Oncogene 22:2226–2235, 2003.

    Article  CAS  PubMed  Google Scholar 

  273. Duval, A. and Hamelin, R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res. 62:2447–2454, 2002.

    CAS  PubMed  Google Scholar 

  274. Malkhosyan, S., Rampino, N., Yamamoto, H., and Perucho, M. Frameshift mutator mutations. Nature 382:499–500, 1996.

    Article  CAS  PubMed  Google Scholar 

  275. Lee, W. H., Bookstein, R., Hong, F., Young, L. J., Shew, J. Y., and Lee, E. Y. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235:1394–1399, 1987.

    Article  CAS  PubMed  Google Scholar 

  276. Liu, H., Dibling, B., Spike, B., Dirlam, A., and Macleod, K. New roles for the RB tumor suppressor protein. Curr. Opin. Genet. Dev. 14:55–64, 2004.

    Article  PubMed  CAS  Google Scholar 

  277. Li, F. P. and Fraumeni, J. F., Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann. Intern. Med. 71:747–752, 1969.

    CAS  PubMed  Google Scholar 

  278. Li, F. P., Fraumeni, J. F., Jr., Mulvihill, J. J., et al. A cancer family s yn-drome in twenty-four kindreds. Cancer Res. 48:5358–5362, 1988.

    CAS  PubMed  Google Scholar 

  279. Li, F. P. and Fraumeni, J. F., Jr. Prospective study of a family cancer syndrome. JAMA 247:2692–2694, 1982.

    Article  CAS  PubMed  Google Scholar 

  280. Lustbader, E. D., Williams, W. R., Bondy, M. L., Strom, S., and Strong, L. C. Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients. Am. J. Hum. Genet. 51:344–356, 1992.

    CAS  PubMed  Google Scholar 

  281. Malkin, D., Li, F. P., Strong, L. C., et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238, 1990.

    Article  CAS  PubMed  Google Scholar 

  282. Srivastava, S., Zou, Z. Q., Pirollo, K., Blattner, W., and Chang, E. H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li–Fraumeni syndrome. Nature 348:747–749, 1990.

    Article  CAS  PubMed  Google Scholar 

  283. Varley, J. M. Germline TP53 mutations and Li-Fraumeni syndrome. Hum. Mutat. 21:313–320, 2003.

    Article  CAS  PubMed  Google Scholar 

  284. Malkin, D. Li–Fraumeni syndrome, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 849–864.

    Google Scholar 

  285. Momand, J., Zambetti, G. P., Olson, D. C., George, D., and Levine, A. J. (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245, 1992.

    CAS  PubMed  Google Scholar 

  286. Coleman, W. B., and Tsongalis, G. J. Cancer epidemiology: incidence and etiology of human neoplasms, in The Molecular Basis of Human Cancer, Coleman, W. B., and Tsongalis, G. J., eds., Humana Pr, Totowa, NJ, 2002, pp. 3–22.

    Google Scholar 

  287. Lynch, H. T. and de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348:919–932, 2003.

    Article  CAS  PubMed  Google Scholar 

  288. Nagase, H., Miyoshi, Y., Horii, A., et al. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res. 52:4055–4057, 1992.

    CAS  PubMed  Google Scholar 

  289. Su, L. K., Johnson, K. A., Smith, K. J., Hill, D. E., Vogelstein, B., and Kinzler, K. W. Association between wild type and mutant APC gene products. Cancer Res. 53:2728–2731, 1993.

    CAS  PubMed  Google Scholar 

  290. Boland, C. R. Hereditary nonpolyposis colorectal cancer (HNPCC), in The Metabolic and Molecular Bases of Inherited Disease 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Va lle, D., eds., McGraw-Hill, New York, 2001, pp. 769–784.

    Google Scholar 

  291. Peltomaki, P., Aaltonen, L. A., Sistonen, P., et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812, 1993.

    Article  CAS  PubMed  Google Scholar 

  292. Parsons, R., Li, G. M., Longley, M., et al. Mismatch repair deficiency in phenotypically normal human cells. Science 268:738–740, 1995.

    Article  CAS  PubMed  Google Scholar 

  293. Peltomaki, P. and de la Chapelle, A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv. Cancer Res. 71:93–119, 1997.

    Article  CAS  PubMed  Google Scholar 

  294. Schwartz, R. A. and Torre, D. P. The Muir–Torre syndrome: a 25-year retrospect. J. Am. Acad. Dermatol. 33:90–104, 1995.

    Article  CAS  PubMed  Google Scholar 

  295. Honchel, R., Halling, K. C., Schaid, D. J., Pittelkow, M., Thibodeau, and S. N. Microsatellite instability in Muir-Torre syndrome. Cancer Res. 54:1159–1163, 1994.

    CAS  PubMed  Google Scholar 

  296. Turcot, J., Despres, J. P., and St Pierre, F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis. Colon Rectum 2:465–468, 1959.

    Article  CAS  PubMed  Google Scholar 

  297. Hamilton, S. R., Liu, B., Parsons, R. E., et al. The molecular basis of Turcot’s syndrome. N. Engl. J. Med. 332:839–847, 1995.

    Article  CAS  PubMed  Google Scholar 

  298. Miki, Y., Swensen, J., Shattuck-Eidens, D., et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71, 1994.

    Article  CAS  PubMed  Google Scholar 

  299. Wooster, R., Bignell, G., Lancaster, J., et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792, 1995.

    Article  CAS  PubMed  Google Scholar 

  300. Sobol, H., Birnbaum, D., and Eisinger, F. Evidence for a third breast-cancer susceptibility gene. Lancet 344:1151–1152, 1994.

    Article  CAS  PubMed  Google Scholar 

  301. Antoniou, A. C., Pharoah, P. D., McMullan, G., et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br. J. Cancer 86:76–83, 2002.

    Article  CAS  PubMed  Google Scholar 

  302. Thompson, D., Szabo, C. I., Mangion, J., et al. Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc. Natl. Acad. Sci. USA 99:827–831, 2002.

    Article  CAS  PubMed  Google Scholar 

  303. Easton, D. F., Ford, D., and Bishop, D. T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 56:265–271, 1995.

    CAS  PubMed  Google Scholar 

  304. Ford, D., Easton, D. F., and Peto, J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am. J. Hum. Genet. 57:1457–1462, 1995.

    CAS  PubMed  Google Scholar 

  305. Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182, 2002.

    Article  CAS  PubMed  Google Scholar 

  306. Welcsh, P. L., and King, M. C. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum. Mol. Genet. 10:705–713, 2001.

    Article  CAS  PubMed  Google Scholar 

  307. Futreal, P. A., Liu, Q., Shattuck-Eidens, D., et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120–122, 1994.

    Article  CAS  PubMed  Google Scholar 

  308. Shattuck-Eidens, D., McClure, M., Simard, J., et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA 273:535–541, 1995.

    Article  CAS  PubMed  Google Scholar 

  309. Gayther, S. A., Warren, W., Mazoyer, S., et al. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation. Nat. Genet. 11:428–433, 1995.

    Article  CAS  PubMed  Google Scholar 

  310. Albino, A. P. Genes involved in melanoma susceptibility and progression. Curr. Opin. Oncol. 7:162–169, 1995.

    Article  CAS  PubMed  Google Scholar 

  311. Bale, S. J., Chakravarti, A., and Greene, M. H. Cutaneous malignant melanoma and familial dysplastic nevi: evidence for autosomal dominance and pleiotropy. Am. J. Hum. Genet. 38:188–196, 1986.

    CAS  PubMed  Google Scholar 

  312. Cannon-Albright, L. A., Goldgar, D. E., Meyer, L. J., et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science 258:1148–1152, 1992.

    Article  CAS  PubMed  Google Scholar 

  313. Goldstein, A. M., Dracopoli, N. C., Ho, E. C., et al. Further evidence for a locus for cutaneous malignant melanoma–dysplastic nevus (CMM/DN) on chromosome 1p, and evidence for genetic heterogeneity. Am. J. Hum. Genet. 52:537–550, 1993.

    CAS  PubMed  Google Scholar 

  314. Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440, 1994.

    Article  CAS  PubMed  Google Scholar 

  315. Hussussian, C. J., Struewing, J. P., Goldstein, A. M., et al. Germline p16 mutations in familial melanoma. Nat. Genet. 8:15–21, 1994.

    Article  CAS  PubMed  Google Scholar 

  316. Kamb, A., Shattuck-Eidens, D., Eeles, R., et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat. Genet. 8:23–26, 1994.

    Article  CAS  PubMed  Google Scholar 

  317. Ohta, M., Nagai, H., Shimizu, M., et al. Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene, CDK4I, in melanoma. Cancer Res. 54:5269–5272, 1994.

    CAS  PubMed  Google Scholar 

  318. Zuo, L., Weger, J., Yang, Q., et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat. Genet. 12:97–99, 1996.

    Article  CAS  PubMed  Google Scholar 

  319. Bressac-de-Paillerets, B., Avril, M. F., Chompret, A., and Demenais, F. Genetic and environmental factors in cutaneous malignant melanoma. Biochimie 84:67–74, 2002.

    Article  CAS  PubMed  Google Scholar 

  320. Tucker, M. A. and Goldstein, A. M. Melanoma etiology: where are we? Oncogene 22:3042–3052, 2003.

    Article  CAS  PubMed  Google Scholar 

  321. Gutmann, D. H. and Collins, F. C. Neurofibromatosis 1, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Va lle, D., eds., McGraw-Hill, New York, 2001, pp. 877–896.

    Google Scholar 

  322. Goldgar, D. E., Green, P., Parry, D. M., and Mulvihill, J. J. Multipoint linkage analysis in neurofibromatosis type I: an international collaboration. vAm. J. Hum. Genet. 44:6–12, 1989.

    CAS  Google Scholar 

  323. Cawthon, R. M., Weiss, R., Xu, G. F., et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62:193–201, 1990.

    Article  CAS  PubMed  Google Scholar 

  324. Viskochil, D., Buchberg, A. M., Xu, G., et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62:187–192, 1990.

    Article  CAS  PubMed  Google Scholar 

  325. Wallace, M. R., Marchuk, D. A., Andersen, L. B., et al. Type 1 neu-rofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186, 1990.

    Article  CAS  PubMed  Google Scholar 

  326. Xu, G. F., O ’Connell, P., Viskochil, D., et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608, 1990.

    Article  CAS  PubMed  Google Scholar 

  327. Kluwe, L., Siebert, R., Gesk, S., Friedrich, R. E., et al. Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum. Mutat. 23:111–116, 2004.

    Article  CAS  PubMed  Google Scholar 

  328. Upadhyaya, M., Han, S., Consoli, C., et al. Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. Hum. Mutat. 23:134–146, 2004

    Article  CAS  PubMed  Google Scholar 

  329. Ponder, B. A. J. Multiple endocrine neoplasia type 2, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 931–942.

    Google Scholar 

  330. Carlson, K. M., Dou, S., Chi, D., et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc. Natl. Acad. Sci. USA 91:1579–1583, 1994.

    Article  CAS  PubMed  Google Scholar 

  331. Haber, D. A. Wilms tumor, in The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds., McGraw-Hill, New York, 2001, pp. 865–876.

    Google Scholar 

  332. Call, K. M., Glaser, T., Ito, C. Y., et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms ’ tumor locus. Cell 60:509–520, 1990.

    Article  CAS  PubMed  Google Scholar 

  333. Gessler, M., Poustka, A., Cavenee, W., Neve, R. L., Orkin, S. H., and Bruns, G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778, 1990.

    Article  CAS  PubMed  Google Scholar 

  334. Royer-Pokora, B., Beier, M., Henzler, M., et al. Twenty-four new cases of WT1 germline mutations and review of the literature: geno-type/phenotype correlations for Wilms tumor development. Am. J. Med. Genet. 127A:249–257, 2004.

    Article  PubMed  Google Scholar 

  335. Etzioni, R., Urban, N., Ramsey, S., et al. The case for early detection. Nat. Rev. Cancer 3:243–252, 2003.

    Article  CAS  PubMed  Google Scholar 

  336. Levin, B. Colorectal cancer screening. Cancer 72:1056–1060, 1993.

    Article  CAS  PubMed  Google Scholar 

  337. Sidransky, D., Tokino, T., Hamilton, S. R., et al. Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science 256:102–105, 1992.

    Article  CAS  PubMed  Google Scholar 

  338. Tobi, M., Luo, F. C., and Ronai, Z. Detection of K-ras mutation in colonic effluent samples from patients without evidence of colorec-tal carcinoma. J. Natl. Cancer Inst. 86:1007–1010, 1994.

    Article  CAS  PubMed  Google Scholar 

  339. Deuter, R., and Muller, O. Detection of APC mutations in stool DNA of patients with colorectal cancer by HD-PCR. Hum. Mutat. 11:84–89, 1998.

    Article  CAS  PubMed  Google Scholar 

  340. Eguchi, S., Kohara, N., Komuta, K., and Kanematsu, T. Mutations of the p53 gene in the stool of patients with resectable colorectal cancer. Cancer 77:1707–1710, 1996.

    CAS  PubMed  Google Scholar 

  341. Minamoto, T., Mai, M., and Ronai, Z. K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancersa —review. Cancer Detect. Prev. 24:1–12, 2000.

    CAS  PubMed  Google Scholar 

  342. Dong, S. M., Traverso, G., Johnson, C., et al. Detecting colorectal cancer in stool with the use of multiple genetic targets. J. Natl. Cancer Inst. 93:858–865, 2001.

    Article  CAS  PubMed  Google Scholar 

  343. Powell, S. M., Petersen, G. M., Krush, A. J., et al. Molecular diagnosis of familial adenomatous polyposis. N. Engl. J. Med. 329:1982–1987, 1993.

    Article  CAS  PubMed  Google Scholar 

  344. Nissum, M., Preuss, D., Harig, A., et al. High-throughput genetic screening using matrix-assisted laser desorption/ionization mass spectrometry. Psychiatr. Genet. 12:109–117, 2002.

    Article  PubMed  Google Scholar 

  345. Bonk, T., Humeny, A., Sutter, C., Gebert, J., von Knebel Doeberitz, M., and Becker, C. M. Molecular diagnosis of familial adenomatous polyposis (FAP): genotyping of adenomatous polyposis coli (APC) alleles by MALDI-TOF mass spectrometry. Clin. Biochem. 35:87–92, 2002.

    Article  CAS  PubMed  Google Scholar 

  346. Mao, L., Hruban, R. H., Boyle, J. O., Tockman, M., and Sidransky, D. Detection of oncogene mutations in sputum precedes diagnosis of lung cancer. Cancer Res. 54:1634–1637, 1994.

    CAS  PubMed  Google Scholar 

  347. Andriani, F., Conte, D., Mastrangelo, T., et al. Detecting lung cancer in plasma with the use of multiple genetic markers. Int. J. Cancer 108:91–96, 2004

    Article  CAS  PubMed  Google Scholar 

  348. Kimura, T., Holland, W. S., Kawaguchi, T., et al. Mutant DNA in plasma of lung cancer patients: potential for monitoring response to therapy. Ann. NY Acad. Sci. 1022:55–60, 2004.

    Article  CAS  PubMed  Google Scholar 

  349. Almoguera, C., Shibata, D., Forrester, K., Martin, J., Arnheim, N., and Perucho, M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554, 1988.

    Article  CAS  PubMed  Google Scholar 

  350. Urban, T., Ricci, S., Grange, J. D., et al. Detection of c-Ki-ras mutation by PCR/RFLP analysis and diagnosis of pancreatic adenocarci-nomas. J. Natl. Cancer Inst. 85:2008–2012, 1993.

    Article  CAS  PubMed  Google Scholar 

  351. Berthelemy, P., Bouisson, M., Escourrou, J., Vaysse, N., Rumeau, J. L., and Pradayrol, L. Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann. Intern. Med. 123:188–191, 1995.

    CAS  PubMed  Google Scholar 

  352. Caldas, C., Hahn, S. A., Hruban, R. H., Redston, M. S., Ye o, C. J., and Kern, S. E. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res. 54:3568–3573, 1994.

    CAS  PubMed  Google Scholar 

  353. Tada, M., Omata, M., Kawai, S., et al. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 53:2472–2474, 1993.

    CAS  PubMed  Google Scholar 

  354. Goh, H. S., Yao, J., and Smith, D. R. p53 point mutation and survival in colorectal cancer patients. Cancer Res. 55, 5217–5221, 1995.

    CAS  PubMed  Google Scholar 

  355. Jen, J., Kim, H., Piantadosi, S., et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med. 331:213–221, 1994.

    Article  CAS  PubMed  Google Scholar 

  356. Borresen-Dale, A. L. TP53 and breast cancer. Hum. Mutat. 21:292–300, 2003.

    Article  CAS  PubMed  Google Scholar 

  357. Saitoh, S., Cunningham, J., De Vries, E. M., et al. p53 gene mutations in breast cancers in midwestern US women: null as well as missense-type mutations are associated with poor prognosis. Oncogene 9:2869–2875, 1994.

    CAS  PubMed  Google Scholar 

  358. Thorlacius, S., Borresen, A. L., and Eyfjord, J. E. Somatic p53 mutations in human breast carcinomas in an Icelandic population: a prognostic factor. Cancer Res. 53:1637–1641, 1993.

    CAS  PubMed  Google Scholar 

  359. Kovach, J. S., Hartmann, A., Blaszyk, H., Cunningham, J., Schaid, D., and Sommer, S. S. Mutation detection by highly sensitive methods indicates that p53 gene mutations in breast cancer can have important prognostic value. Proc. Natl. Acad. Sci. USA 93:1093–1096, 1996.

    Article  CAS  PubMed  Google Scholar 

  360. Fielding, L. P. and Pettigrew, N. College of American Pathologists Conference XXVI on clinical relevance of prognostic markers in solid tumors. Report of the Colorectal Cancer Working Group. Arch. Pathol. Lab. Med. 119:1115–1121, 1995.

    CAS  PubMed  Google Scholar 

  361. Hammond, M. E., Fitzgibbons, P. L., Compton, C. C., et al. College of American Pathologists Conference XXXV: solid tumor prognostic factorsw —hich, how and so what? Summary document and recommendations for implementation. Cancer Committee and Conference Participants. Arch. Pathol. Lab. Med. 124:958–965, 2000.

    CAS  PubMed  Google Scholar 

  362. Henson, D. E., Fielding, L. P., Grignon, D. J., et al. College of American Pathologists Conference XXVI on clinical relevance of prognostic markers in solid tumors. Summary. Members of the Cancer Committee. Arch. Pathol. Lab. Med. 119:1109–1112, 1995.

    CAS  PubMed  Google Scholar 

  363. Grignon, D. J. and Hammond, E. H. College of American Pathologists Conference XXVI on clinical relevance of prognostic markers in solid tumors. Report of the Prostate Cancer Working Group. Arch. Pathol. Lab. Med. 119:1122–1126, 1995.

    CAS  PubMed  Google Scholar 

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Coleman, W.B., Tsongalis, G.J. (2006). Molecular Pathogenesis of Human Cancer. In: Coleman, W.B., Tsongalis, G.J. (eds) Molecular Diagnostics. Humana Press. https://doi.org/10.1385/1-59259-928-1:349

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