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Genetic instabilities in human cancers

Abstract

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

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Figure 1: Examples of genetic alterations in cancer.
Figure 2: Pathways to genetic instability.
Figure 3: Increased mutation rates at the HPRT locus in MIN versus CIN cancer cell lines (ref. 41and J. Eshleman, M. Veigl, D. Sedwick and S. Markowitz, personal communication).
Figure 4: Frequency of allelic losses in MIN versus CIN cancers.
Figure 5: Cellular processes involved in replication and segregation of chromosomes during mitosis.

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References

  1. Loeb, L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).

    CAS  PubMed  Google Scholar 

  2. Hartwell, L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71, 543–546 (1992).

    CAS  PubMed  Google Scholar 

  3. Tomlinson, I. P., Novelli, M. R. & Bodmer, W. F. The mutation rate and cancer. Proc. Natl Acad. Sci. USA 93, 14800–14803 (1996).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Almoguera, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53, 549–554 (1988).

    CAS  PubMed  Google Scholar 

  5. Mitelman, F., Johansson, B. & Mertens, F. Catalog of Chromosome Aberrations in Cancer Vol. 2(Wiley-Liss, New York, (1994)).

    Google Scholar 

  6. Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183–4186 (1997).

    CAS  PubMed  Google Scholar 

  7. Zhuang, Z. et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genet. 20, 66–69 (1998).

    CAS  PubMed  Google Scholar 

  8. Nowell, P. C. Genetic alterations in leukemias and lymphomas: impressive progress and continuing complexity. Cancer Genet. Cytogenet. 94, 13–19 (1997).

    CAS  PubMed  Google Scholar 

  9. Brodeur, G. M. & Hogarty, M. D. in The Genetic Basis of Human Cancer 1st edn Vol. 1(eds Kinzler, K. W. & Vogelstein, B.) 161–179 (McGraw-Hill, New York, (1998)).

    Google Scholar 

  10. Seeger, R. C. et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N. Engl. J. Med. 313, 1111–1116 (1985).

    CAS  PubMed  Google Scholar 

  11. Kauffmann-Zeh, A. et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385, 544–548 (1997).

    ADS  CAS  PubMed  Google Scholar 

  12. Kunkel, T. A. DNA-mismatch repair. The intricacies of eukaryotic spell-checking. Curr. Biol. 5, 1091–1094 (1995).

    CAS  PubMed  Google Scholar 

  13. Sia, E. A., Jinks-Robertson, S. & Petes, T. D. Genetic control of microsatellite stability. Mutat. Res. 383, 61–70 (1997).

    CAS  PubMed  Google Scholar 

  14. Cleaver, J. E. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218, 652–656 (1968).

    ADS  CAS  PubMed  Google Scholar 

  15. De Weerd-Kastelein, E. A., Keijzer, W. & Bootsma, D. Genetic heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization. Nat. New Biol. 238, 80–83 (1972).

    CAS  PubMed  Google Scholar 

  16. Bootsma, D., Kraemer, K. H., Cleaver, J. E. & Hoeijmakers, J. H. J. in The Genetic Basis of Human Cancer(eds Kinzler, K. W. & Vogelstein, B.) 245–274 (McGraw-Hill, New York, (1998)).

    Google Scholar 

  17. Wood, R. D. DNA repair in eukaryotes. Annu. Rev. Biochem. 65, 135–167 (1996).

    CAS  PubMed  Google Scholar 

  18. Cairns, J. The origin of human cancers. Nature 289, 353–357 (1981).

    ADS  CAS  PubMed  Google Scholar 

  19. Feinberg, A. P. & Coffey, D. S. Organ site specificity for cancer in chromosomal instability disorders. Cancer Res. 42, 3252–3254 (1982).

    CAS  PubMed  Google Scholar 

  20. Kraemer, K. H., Lee, M. M. & Scotto, J. DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum. Carcinogenesis 5, 511–514 (1984).

    CAS  PubMed  Google Scholar 

  21. Ames, B. N. & Gold, L. S. Endogenous mutagens and the causes of aging and cancer. Mutat. Res. 250, 3–16 (1991).

    CAS  PubMed  Google Scholar 

  22. Peinado, M. A., Malkhosyan, S., Velazquez, A. & Perucho, M. Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc. Natl Acad. Sci. USA 89, 10065–10069 (1992).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  24. Thibodeau, S. N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).

    ADS  CAS  PubMed  Google Scholar 

  25. Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).

    ADS  CAS  PubMed  Google Scholar 

  26. Peltomaki, P. et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810–812 (1993).

    ADS  CAS  PubMed  Google Scholar 

  27. Lindblom, A., Tannergard, P., Werelius, B. & Nordenskjold, M. Genetic mapping of a second locus predisoposing to hereditary non-polyposis colon cancer. Nature Genet. 5, 279–282 (1993).

    CAS  PubMed  Google Scholar 

  28. Strand, M., Prolla, T. A., Liskay, R. M. & Petes, T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365, 274–276 (1993).

    ADS  CAS  PubMed  Google Scholar 

  29. Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    CAS  PubMed  Google Scholar 

  30. Leach, F. S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).

    CAS  PubMed  Google Scholar 

  31. Bronner, C. E. et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368, 258–261 (1994).

    ADS  CAS  PubMed  Google Scholar 

  32. Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).

    ADS  CAS  PubMed  Google Scholar 

  33. Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993).

    CAS  PubMed  Google Scholar 

  34. Umar, A. et al. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J. Biol. Chem. 269, 14367–14370 (1994).

    CAS  PubMed  Google Scholar 

  35. Peltomaki, P. & de la Chapelle, A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv. Cancer Res. 71, 93–119 (1997).

    CAS  PubMed  Google Scholar 

  36. Modrich, P. Mismatch repair, genetic stability and tumour avoidance. Phil. Trans. R. Soc. Lond. B 347, 89–95 (1995).

    ADS  CAS  Google Scholar 

  37. Kolodner, R. Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev. 10, 1433–1442 (1996).

    CAS  PubMed  Google Scholar 

  38. Perucho, M. Cancer of the microsatellite mutator phenotype. Biol. Chem. 377, 675–684 (1996).

    CAS  PubMed  Google Scholar 

  39. Dams, E., Van de Kelft, E. J., Martin, J. J., Verlooy, J. & Willems, P. J. Instability of microsatellites in human gliomas. Cancer Res. 55, 1547–1549 (1995).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Eshleman, J. R. et al. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10, 33–37 (1995).

    CAS  PubMed  Google Scholar 

  42. Vogelstein, B. et al. Allelotype of colorectal carcinomas. Science 244, 207–211 (1989).

    ADS  CAS  PubMed  Google Scholar 

  43. Boige, V. et al. Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype. Cancer Res. 57, 1986–1990 (1997).

    CAS  PubMed  Google Scholar 

  44. Seymour, A. B. et al. Allelotype of pancreatic adenocarcinoma. Cancer Res. 54, 2761–2764 (1994).

    CAS  PubMed  Google Scholar 

  45. Radford, D. M. et al. Allelotyping of ductal 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 

  46. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627 (1997).

    ADS  CAS  PubMed  Google Scholar 

  47. Phear, G., Bhattacharyya, N. P. & Meuth, M. Loss of heterozygosity 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  PubMed Central  Google Scholar 

  48. Bardi, G. et al. Cytogenetic comparisons of synchronous carcinomas and polyps in patients with colorectal cancer. Br. J. Cancer. 76, 765–769 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Silverstein, M. J. Ductal Carcinoma in situ of the Breast(Williams & Wilkins, Baltimore, (1997)).

    Google Scholar 

  50. Bomme, L. et al. Cytogenetic analysis of colorectal adenomas: karyotypic comparisons of synchronous tumors. Cancer Genet. Cytogenet. 106, 66–71 (1998).

    CAS  PubMed  Google Scholar 

  51. Aaltonen, L. A. et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res. 54, 1645–1648 (1994).

    CAS  PubMed  Google Scholar 

  52. Koi, M. 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 

  53. Li, R. et al. Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells. Proc. Natl Acad. Sci. USA 94, 14506–14511 (1997).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Harvey, M. et al. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8, 2457–2467 (1993).

    CAS  PubMed  Google Scholar 

  55. Cross, S. M. et al. Ap53-dependent mouse spindle checkpoint. Science 267, 1353–1356 (1995).

    ADS  CAS  PubMed  Google Scholar 

  56. Lanni, J. S. & Jacks, T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell. Biol. 18, 1055–1064 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Eshleman, J. R. 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).

    CAS  PubMed  Google Scholar 

  58. Baker, S. J. 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 

  59. Auer, G. U., Heselmeyer, K. M., Steinbeck, R. G., Munck-Wikland, E. & Zetterberg, A. D. The relationship between aneuploidy and p53 overexpression during genesis of colorectal adenocarcinoma. Virchows Arch. 424, 343–347 (1994).

    CAS  PubMed  Google Scholar 

  60. Hoyt, M. A., Stearns, T. & Botstein, D. Chromosome instability mutants of Saccharomyces cerevisiae that are defective in microtubule-mediated processes. Mol. Cell. Biol. 10, 223–234 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Spencer, F., Gerring, S. L., Connelly, C. & Hieter, P. Mitotic chromosome transmission fidelity mutants in Saccharomyces cerevisiae. Genetics 124, 237–249 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Murray, A. W. The genetics of cell cycle checkpoints. Curr. Opin. Genet. Dev. 5, 5–11 (1995).

    CAS  PubMed  Google Scholar 

  63. Nasmyth, K. At the heart of the budding yeast cell cycle. Trends Genet. 12, 405–412 (1996).

    CAS  PubMed  Google Scholar 

  64. Elledge, S. J. Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664–1672 (1996).

    ADS  CAS  PubMed  Google Scholar 

  65. Paulovich, A. G., Toczyski, D. P. & Hartwell, L. H. When checkpoints fail. Cell 88, 315–321 (1997).

    CAS  PubMed  Google Scholar 

  66. Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).

    ADS  CAS  PubMed  Google Scholar 

  67. Li, Y. & Benezra, R. Identification of a human mitotic checkpoint gene: hsMAD2. Science 274, 246–248 (1996).

    ADS  CAS  PubMed  Google Scholar 

  68. Taylor, S. S. & McKeon, F. Kenetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89, 727–735 (1997).

    CAS  PubMed  Google Scholar 

  69. Jin, D. Y., Spencer, F. & Jeang, K. T. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 93, 81–91 (1998).

    CAS  PubMed  Google Scholar 

  70. Hartwell, L. H. & Smith, D. Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae. Genetics 110, 381–395 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Rotman, G. & Shiloh, Y. ATM: from gene to function. Hum. Mol. Genet. 7, 1555–1563 (1998).

    CAS  PubMed  Google Scholar 

  72. Smith, L. et al. Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest. Nature Genet. 19, 39–46 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  74. Lane, D. Awakening angels. Nature 394, 616–617 (1998).

    ADS  CAS  PubMed  Google Scholar 

  75. Doxsey, S. The centrosome — a tiny organelle with big potential. Nature Genet. 20, 104–106 (1998).

    CAS  PubMed  Google Scholar 

  76. Zhou, H. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genet. 20, 189–193 (1998).

    CAS  PubMed  Google Scholar 

  77. Bischoff, J. R. et al. Ahomologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17, 3052–3065 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G. F. Abnormal centrosome amplification in the absence of p53. Science 271, 1744–1747 (1996).

    ADS  CAS  PubMed  Google Scholar 

  80. Johansson, B., Mertens, F. & Mitelman, F. Primary vs. secondary neoplasia-associated chromosomal abnormalities — balanced rearrangements vs. genomic imbalances? Genes Chromosomes Cancer 16, 155–163 (1996).

    CAS  PubMed  Google Scholar 

  81. Sturzbecher, H. W., Donzelmann, B., Henning, W., Knippschild, U. & Buchhop, S. p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J. 15, 1992–2002 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Mekeel, K. L. et al. Inactivation of p53 results in high rates of homologous recombination. Oncogene 14, 1847–1857 (1997).

    CAS  PubMed  Google Scholar 

  83. Le Beau, M. M. & Rowley, J. D. Chromosomal abnormalities in leukemia and lymphoma: clinical and biological significance. Adv. Hum. Genet. 15, 1–54 (1986).

    CAS  PubMed  Google Scholar 

  84. Tycko, B., Palmer, J. D. & Sklar, J. Tcell receptor gene trans-rearrangements: chimeric gamma-delta genes in normal lymphoid tissues. Science 245, 1242–1246 (1989).

    ADS  CAS  PubMed  Google Scholar 

  85. Hiom, K., Melek, M. & Gellert, M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocaitons. Cell 94, 463–470 (1998).

    CAS  PubMed  Google Scholar 

  86. Tlsty, T. D., Margolin, B. H. & 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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Livingston, L. R. et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).

    Google Scholar 

  88. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  90. Pegram, M. D. et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16, 2659–2671 (1998).

    CAS  PubMed  Google Scholar 

  91. Owens, A. H., Coffey, D. S. & Baylin, S. B. Tumor Cell Heterogeneity(Academic, New York, (1982)).

    Google Scholar 

  92. Abbott, D. W., Freeman, M. L. & Holt, J. T. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J. Natl Cancer Inst. 90, 978–985 (1998).

    CAS  PubMed  Google Scholar 

  93. Waldman, T., Lengauer, C., Kinzler, K. W. & Vogelstein, B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381, 713–716 (1996).

    ADS  CAS  PubMed  Google Scholar 

  94. Williams, C. et al. Clones of normal keratinocytes and a variety of simultaneously present epidermal neoplastic lesions contain a multitude of p53 gene mutations in a xeroderma pigmentosum patient. Cancer Res. 58, 2449–2455 (1998).

    CAS  PubMed  Google Scholar 

  95. Markowitz, S. et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Markowitz and A. Weith for sharing unpublished data, and our colleagues in the Molecular Genetics Laboratory for reviewing the manuscript. This work was supported by the Clayton Fund and grants from the National Cancer Institute.

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Lengauer, C., Kinzler, K. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998). https://doi.org/10.1038/25292

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