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Genomic instability — an evolving hallmark of cancer

Key Points

  • Genomic instability is a characteristic of most cancers. Insight into the possible mechanisms leading to genomic instability can be gained by reviewing the recent high-throughput sequencing studies of human cancers.

  • In hereditary cancers, characterized either by microsatellite instability or chromosomal instability, the underlying basis for the genomic instability is mutations in DNA repair genes.

  • In sporadic (non-hereditary) cancers, genomic instability, at least at the early stages of cancer development, is not due to mutations in DNA repair genes or mitotic checkpoint genes.

  • The pattern of mutations in sporadic human cancers suggests that the selective pressure for tumour suppressor p53 (TP53) mutations is linked to DNA damage, rather than p14ARF activation.

  • Genomic instability in sporadic human cancers may be linked to oncogene-induced DNA damage.

  • Analysis of the recent high-throughput sequencing studies of human cancers suggests that genomic instability can be added to the original hallmarks of cancer, and that two previously distinct hallmarks, self-sufficiency in growth signals and insensitivity to anti-growth signals, can be consolidated into one.

Abstract

Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

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Figure 1: Mutations in p53 pathway genes are mutually exclusive with ATM, but not CDKN2A, mutations.
Figure 2: Genomic instability as a hallmark of cancer.

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References

  1. Von Hansemann, D. Ueber asymmetrische Zellteilung in Epithelkrebsen und deren biologische Bedeutung. Virchows Arch. Patholog. Anat. 119, 299–326 (1890) (in German).

    Article  Google Scholar 

  2. Boveri, T. in Zur frage der enstehung maligner tumoren (Gustav Fischer Verlag, Jena, 1914) (in German).

    Google Scholar 

  3. Winge, O. Zytologische untersuchungen uber die natur maligner tumoren. II. Teerkarzinome bei mausen. Z. Zellforsch. Mikrosk. Anat. 10, 683–735 (1930) (in German).

    Article  Google Scholar 

  4. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976). Discussion of the presence of genomic instability in tumours and its role in cancer progression.

    Article  CAS  PubMed  Google Scholar 

  5. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627, 1997. Evidence for the presence of genomic instability in cancers.

    Article  CAS  PubMed  Google Scholar 

  6. Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993). Provides evidence that mutations in DNA repair genes underlie genomic instability in hereditary cancers.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Al-Tassan, N. et al. Inherited variants of MYH associated with somatic G:C–T:A mutations in colorectal tumors. Nature Genet. 30, 227–232 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Kennedy, R. D. & D'Andrea, A. D. DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. J. Clin. Oncol. 24, 3799–3808 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Ripperger, T., Gadzicki, D., Meindl, A. & Schlegelberger, B. Breast cancer susceptibility: current knowledge and implications for genetic counselling. Eur. J. Hum. Genet. 17, 722–731 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Bachrati, C. Z. & Hickson, I. D. RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem. J. 374, 577–606 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cleaver, J. E. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nature Rev. Cancer 5, 564–573 (2005).

    Article  CAS  Google Scholar 

  13. Loeb, L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991). A description of the mutator hypothesis.

    CAS  PubMed  Google Scholar 

  14. Kinzler, K. W. & Vogelstein, B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 386, 761–763 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Rajagopalan, H. & Lengauer, C. Aneuploidy and cancer. Nature 432, 338–341 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58, 181–187 (1999). Shows that there is a low frequency of mutations in mitotic checkpoint genes in human cancers.

    Article  CAS  PubMed  Google Scholar 

  18. Wang, Z. et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res. 64, 2998–3001 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008). Description of the oncogene-induced DNA replication stress model.

    Article  CAS  PubMed  Google Scholar 

  20. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005). References 20 and 21 analyse human precancerous lesions, providing evidence in support of the oncogene-induced DNA replication stress model.

    Article  CAS  PubMed  Google Scholar 

  22. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  PubMed  Google Scholar 

  25. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  29. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008). References 24–29 are high-throughput sequencing studies of human cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Parmigiani, G. et al. Design and analysis issues in genome-wide somatic mutation studies of cancer. Genomics 93, 17–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Lee, W., Yue, P. & Zhang, Z. Analytical methods for inferring functional effects of single base pair substitutions in human cancers. Hum. Genet. 126, 481–498 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Driscoll, M. Haploinsufficiency of DNA damage response genes and their potential influence in human disorders. Curr. Genomics 9, 137–146 (2008).

    Article  Google Scholar 

  34. Bodmer, W. Genetic instability is not a requirement for tumor development. Cancer Res. 68, 3558–3560 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cahill, D. P., Kinzler, K. W., Vogelstein, B. & Lengauer, C. Genetic instability and darwinian selection in tumours. Trends Cell Biol. 9, M57–M60 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Kuerbitz, S. J., Plunkett, B. S., Walsh, W. V. & Kastan, M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl Acad. Sci. USA 89, 7491–7495 (1992). Evidence that p53 is a DNA damage response protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kang, J. et al. Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression. Mol. Cell. Biol. 25, 661–670 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bunz, F. et al. Targeted inactivation of p53 in human cells does not result in aneuploidy. Cancer Res. 62, 1129–1133 (2002).

    CAS  PubMed  Google Scholar 

  39. Denko, N. C., Giaccia, A. J., Stringer, J. R. & Stambrook, P. J. The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle. Proc. Natl Acad. Sci. USA 91, 5124–5128 (1994). Evidence that oncogenes induce CIN.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mai, S., Fluri, M., Siwarski, D. & Huppi, K. Genomic instability in MycER-activated Rat1A-MycER cells. Chromosome Res. 4, 365–371 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Felsher, D. W. & Bishop, J. M. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc. Natl Acad. Sci. USA 96, 3940–3944 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Spruck, C. H., Won, K. A. & Reed, S. I. Deregulated cyclin E induces chromosome instability. Nature 401, 297–300 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Berkovich, E. & Ginsberg, D. ATM is a target for positive regulation by E2F-1. Oncogene 22, 161–167 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Woo, R. A. & Poon, R. Y. Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation. Genes Dev. 18, 1317–1330 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lengronne, A. & Schwob, E. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G1 . Mol. Cell 9, 1067–1078 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Tanaka, S. & Diffley, J. F. Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation. Genes Dev. 16, 2639–2649 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Durkin, S. G. & Glover, T. W. Chromosome fragile sites. Annu. Rev. Genet. 41, 169–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Tsantoulis, P. K. et al. Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene 27, 3256–3264 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).

    Article  CAS  PubMed  Google Scholar 

  51. Zhang, Y., Xiong, Y. & Yarbrough, W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92, 725–734 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Parant, J. et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genet. 29, 92–95 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Quelle, D. E., Zindy, F., Ashmun, R. A. & Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000 (1995). Identification of p14ARF as the second protein product of CDKN2A.

    Article  CAS  PubMed  Google Scholar 

  55. Matsushime, H. et al. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71, 323–334 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000). Defines the hallmarks of cancer.

    Article  CAS  PubMed  Google Scholar 

  58. Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13, 472–482 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009). Refines the hallmarks of cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  PubMed  Google Scholar 

  63. Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank B. Zhivotovsky for comments on the manuscript. Research in the laboratories of the authors is supported by the EC project GENICA, the Swiss National Science Foundation and the National Institutes of Health, USA.

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Correspondence to Thanos D. Halazonetis.

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Glossary

Hereditary non-polyposis colon cancer

An autosomal dominant disease that is characterized by increased susceptibility to colon carcinoma and other forms of cancer owing to an inherited defect in DNA mismatch repair genes.

DNA mismatch repair

The repair of DNA base-pair mismatches that arise as a result of replication errors or after exposure to several DNA damaging agents.

MYH-associated polyposis

An autosomal recessive disease that predisposes to colorectal cancer and is caused by germline mutations in the DNA repair gene MYH.

Base excision repair

A pathway of DNA repair in which a single damaged base is excised by a DNA glycosylase.

Fanconi anaemia

A rare autosomal recessive disease that is characterized by developmental abnormalities, aplastic anaemia and increased susceptibility to solid and haematopoietic cancers.

Xenograft

A tissue or organ from one species transplanted into another species. The term is derived from the Greek 'Xeno', meaning foreign, and graft.

Glioblastoma

The most frequent and most malignant type of primary brain cancer. It is composed of poorly differentiated neoplastic astrocytes.

Transcription coupled-nucleotide excision repair

The branch of nucleotide excision repair — a pathway that repairs damaged bases by excision of a 25–30-nucleotide stretch of the DNA strand that contains the damaged base or bases — that repairs DNA lesions in the transcribed strands of active genes.

Spindle assembly checkpoint

The checkpoint that monitors the proper attachment of chromosomes to spindle microtubules.

Non-synonymous mutation

A mutation that results in an alteration of the amino acid sequence of a protein.

Fanconi anaemia DNA repair pathway

A pathway that primarily repairs DNA interstrand cross links.

Homologous recombination (HR) repair

The error-free repair of DNA DSBs, in which the broken DNA molecule is repaired using homologous sequences.

Non-homologous end joining

A pathway that repairs DNA DSBs by directly ligating the broken ends, without the need for a homologous template.

Common fragile site

A chromosomal region that is prone to breakage after inhibition of DNA replication.

Proteotoxic stress

A cellular stress that is due to the accumulation of misfolded proteins arising from disequilibrium in the protein homeostatic machinery.

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Negrini, S., Gorgoulis, V. & Halazonetis, T. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11, 220–228 (2010). https://doi.org/10.1038/nrm2858

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