Cancer and Metastasis Reviews

, Volume 32, Issue 3–4, pp 353–361 | Cite as

Do mutator mutations fuel tumorigenesis?

  • Edward J. Fox
  • Marc J. Prindle
  • Lawrence A. LoebEmail author


The mutator phenotype hypothesis proposes that the mutation rate of normal cells is insufficient to account for the large number of mutations found in human cancers. Consequently, human tumors exhibit an elevated mutation rate that increases the likelihood of a tumor acquiring advantageous mutations. The hypothesis predicts that tumors are composed of cells harboring hundreds of thousands of mutations, as opposed to a small number of specific driver mutations, and that malignant cells within a tumor therefore constitute a highly heterogeneous population. As a result, drugs targeting specific mutated driver genes or even pathways of mutated driver genes will have only limited anticancer potential. In addition, because the tumor is composed of such a diverse cell population, tumor cells harboring drug-resistant mutations will exist prior to the administration of any chemotherapeutic agent. We present recent evidence in support of the mutator phenotype hypothesis, major arguments against this concept, and discuss the clinical consequences of tumor evolution fueled by an elevated mutation rate. We also consider the therapeutic possibility of altering the rate of mutation accumulation. Most significantly, we contend that there is a need to fundamentally reconsider current approaches to personalized cancer therapy. We propose that targeting cellular pathways that alter the rate of mutation accumulation in tumors will ultimately prove more effective than attempting to identify and target mutant driver genes or driver pathways.


Mutator phenotype Mutation Heterogeneity Cancer genome sequencing Tumor evolution 



We would like to thank Ashwini Kamath-Loeb and Kate Bayliss-Reid for critical reading of the manuscript and other Loeb lab members for helpful discussions. We thank Diana Lim for constructing Fig. 1. The authors apologize to colleagues whose valuable work, while uncited in this review, has enormous impact on the field. LAL is supported by R01-CA102029, R01-CA160674, and P01-CA077852 from the NCI and P01-AG-033061 from the NIA.

Conflict of interest

The authors declare no conflict(s) of interest.


  1. 1.
    Loeb, L. A., Springgate, C. F., & Battula, N. (1974). Errors in DNA replication as a basis of malignant change. Cancer Research, 34, 2311–2321.PubMedGoogle Scholar
  2. 2.
    Lindahl, T., & Wood, R. D. (1999). Quality control by DNA repair. Science, 286(5446), 1897–1905.PubMedCrossRefGoogle Scholar
  3. 3.
    Miller, J. H., Suthar, A., Tai, J., Yeung, A., Truong, C., & Stewart, J. L. (1999). Direct selection for mutators in Escherichia coli. Journal of Bacteriology, 181(5), 1576–1584.PubMedGoogle Scholar
  4. 4.
    Kolodner, R. D., Putnam, C. D., & Myung, K. (2002). Maintenance of genome stability in Saccharomyces cerevisiae. Science, 297(5581), 552–557.PubMedCrossRefGoogle Scholar
  5. 5.
    Herr, A. J., Ogawa, M., Lawrence, N. A., Williams, L. N., Eggington, J. M., Singh, M., et al. (2011). Mutator suppression and escape from replication error-induced extinction in yeast. PLoS Genetics, 7(10), e1002282.PubMedCrossRefGoogle Scholar
  6. 6.
    Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenberg, S. M., Thulin, C., & Harris, R. S. (1998). Transient and heritable mutators in adaptive evolution in the lab and in nature. Genetics, 148(4), 1559–1566.PubMedGoogle Scholar
  8. 8.
    Armitage, P., & Doll, R. (1954). The age distribution of cancer and a multi-stage theory of carcinogenesis. British Journal of Cancer, 8(1), 1–12.PubMedGoogle Scholar
  9. 9.
    Loeb, L. A., Loeb, K. R., & Anderson, J. P. (2003). Multiple mutations and cancer. Proceedings of the National Academy of Sciences of the United States of America, 100(3), 776–781.PubMedCrossRefGoogle Scholar
  10. 10.
    Heng, H. H., Liu, G., Stevens, J. B., Bremer, S. W., Ye, K. J., & Ye, C. J. (2010). Genetic and epigenetic heterogeneity in cancer: the ultimate challenge for drug therapy. Current Drug Targets, 11(10), 1304–1316.PubMedCrossRefGoogle Scholar
  11. 11.
    Jones, S., Chen, W. D., Parmigiani, G., Diehl, F., Beerenwinkel, N., Antal, T., et al. (2008). Comparative lesion sequencing provides insights into tumor evolution. Proceedings of the National Academy of Sciences of the United States of America, 105(11), 4283–4288.PubMedCrossRefGoogle Scholar
  12. 12.
    Kinzler, K. W., & Vogelstein, B. (1996). Lessons from hereditary colorectal cancer. Cell, 87(2), 159–170.PubMedCrossRefGoogle Scholar
  13. 13.
    Salk, J. J., Fox, E. J., & Loeb, L. A. (2009). Mutational heterogeneity in human cancers: origin and consequences. Annual Reviews of Pathology, 5, 51–75.CrossRefGoogle Scholar
  14. 14.
    Fox, E. J., Salk, J. J., & Loeb, L. A. (2009). Cancer genome sequencing—an interim analysis. Cancer Research, 69(12), 4948–4950.PubMedCrossRefGoogle Scholar
  15. 15.
    Loeb, L. A. (2011). Human cancers express mutator phenotypes: origin, consequences and targeting. Nature Reviews. Cancer, 11(6), 450–457.PubMedCrossRefGoogle Scholar
  16. 16.
    Ding, L., Ley, T. J., Larson, D. E., Miller, C. A., Koboldt, D. C., Welch, J. S., et al. (2012). Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature, 481(7382), 506–510.PubMedCrossRefGoogle Scholar
  17. 17.
    Beckman, R. A., Schemmann, G. S., & Yeang, C. H. (2012). Impact of genetic dynamics and single-cell heterogeneity on development of nonstandard personalized medicine strategies for cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(36), 14586–14591.PubMedCrossRefGoogle Scholar
  18. 18.
    Prindle, M. J., Fox, E. J., & Loeb, L. A. (2010). The mutator phenotype in cancer: molecular mechanisms and targeting strategies. Current Drug Targets, 11(10), 1296–1303.PubMedCrossRefGoogle Scholar
  19. 19.
    Fox, E. J., & Loeb, L. A. (2010). Lethal mutagenesis: targeting the mutator phenotype in cancer. Seminars in Cancer Biology, 20(5), 353–359.PubMedCrossRefGoogle Scholar
  20. 20.
    Sawyers, C. L., Hochhaus, A., Feldman, E., Goldman, J. M., Miller, C. B., Ottmann, O. G., et al. (2002). Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood, 99(10), 3530–3539.PubMedCrossRefGoogle Scholar
  21. 21.
    Boveri, T. (1902). Uber mehrpolige Mitosen als Mittel zur Analyse des Zellkerns. Wurzburg: Veh. Dtsch. Zool. Ges.Google Scholar
  22. 22.
    Kunkel, T. A. (2004). DNA replication fidelity. Journal of Biological Chemistry, 279(17), 16895–16898.PubMedCrossRefGoogle Scholar
  23. 23.
    Modrich, P., & Lahue, R. (1996). Mismatch repair in replication fidelity, genetic recombination and cancer biology. Annual Reviews in Biochemistry, 65, 101–133.CrossRefGoogle Scholar
  24. 24.
    Preston, B. D., Albertson, T. M., & Herr, A. J. (2010). DNA replication fidelity and cancer. Seminars in Cancer Biology, 20(5), 281–293.PubMedCrossRefGoogle Scholar
  25. 25.
    Araten, D. J., Martinez-Climent, J. A., Perle, M. A., Holm, E., Zamechek, L., DiTata, K., et al. (2010). A quantitative analysis of genomic instability in lymphoid and plasma cell neoplasms based on the PIG-A gene. Mutation Research, 686(1–2), 1–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Cleaver, J. E. (1968). Defective repair replication of DNA in Xeroderma pigmentosum. Nature, 218(5142), 652–656.PubMedCrossRefGoogle Scholar
  27. 27.
    Frejter, W. L., McDaniel, L. D., Johns, D., Friedberg, E. C., & Schultz, R. A. (1982). Correction of Xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene. Proceedings of the National Academy of Sciences of the United States of America, 89, 261–265.CrossRefGoogle Scholar
  28. 28.
    Bohr, V. A., Smith, C. A., Okumoto, D. S., & Hanawalt, P. C. (1985). DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell, 40, 359–369.PubMedCrossRefGoogle Scholar
  29. 29.
    Hoogervorst, E. M., van Steeg, H., & de Vries, A. (2005). Nucleotide excision repair- and p53-deficient mouse models in cancer research. Mutation Research, 574(1–2), 3–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Albertson, T. M., Ogawa, M., Bugni, J. M., Hays, L. E., Chen, Y., Wang, Y., et al. (2009). DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice. Proceedings of the National Academy of Sciences of the United States of America, 106(40), 17101–17104.PubMedCrossRefGoogle Scholar
  31. 31.
    Venkatesan, R. N., Hsu, J. J., Lawrence, N. A., Preston, B. D., & Loeb, L. A. (2006). Mutator phenotypes caused by substitution at a conserved motif A residue in eukaryotic DNA polymerase delta. Journal of Biological Chemistry, 281(7), 4486–4494.PubMedCrossRefGoogle Scholar
  32. 32.
    Venkatesan, R. N., Treutin, P. M., Fuller, E. D., Goldsby, R. E., Norwood, T. H., Gooley, T. A., et al. (2007). Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Molecular and Cellular Biology, 27(21), 7669–7682.PubMedCrossRefGoogle Scholar
  33. 33.
    Little, M. P., & Li, G. (2007). Stochastic modelling of colon cancer: is there a role for genomic instability? Carcinogenesis, 28(2), 479–487.PubMedCrossRefGoogle Scholar
  34. 34.
    Merlo, L. M., Pepper, J. W., Reid, B. J., & Maley, C. C. (2006). Cancer as an evolutionary and ecological process. Nature Reviews. Cancer, 6(12), 924–935.PubMedCrossRefGoogle Scholar
  35. 35.
    Nowak, M. A., Michor, F., Komarova, N. L., & Iwasa, Y. (2004). Evolutionary dynamics of tumor suppressor gene inactivation. Proceedings of the National Academy of Sciences of the United States of America, 101(29), 10635–10638.PubMedCrossRefGoogle Scholar
  36. 36.
    Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321(5897), 1807–1812.PubMedCrossRefGoogle Scholar
  37. 37.
    Yates, L. R., & Campbell, P. J. (2012). Evolution of the cancer genome. Nature Reviews Genetics, 13(11), 795–806.PubMedCrossRefGoogle Scholar
  38. 38.
    Treangen, T. J., & Salzberg, S. L. (2012). Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nature Reviews Genetics, 13(1), 36–46.Google Scholar
  39. 39.
    Mahale, A. M., Khan, Z. A., Igarashi, M., Nanjangud, G. J., Qiao, R. F., Yao, S., et al. (2008). Clonal selection in malignant transformation of human fibroblasts transduced with defined cellular oncogenes. Cancer Research, 68(5), 1417–1426.PubMedCrossRefGoogle Scholar
  40. 40.
    Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999). Creation of human tumour cells with defined genetic elements. Nature, 400(6743), 464–468.PubMedCrossRefGoogle Scholar
  41. 41.
    Wang, J., Gonzalez, K. D., Scaringe, W. A., Tsai, K., Liu, N., Gu, D., et al. (2007). Evidence for mutation showers. Proceedings of the National Academy of Sciences of the United States of America, 104(20), 8403–8408.PubMedCrossRefGoogle Scholar
  42. 42.
    Nik-Zainal, S., Alexandrov, L. B., Wedge, D. C., Van Loo, P., Greenman, C. D., Raine, K., et al. (2012). Mutational processes molding the genomes of 21 breast cancers. Cell, 149(5), 979–993.PubMedCrossRefGoogle Scholar
  43. 43.
    Roberts, S. A., Sterling, J., Thompson, C., Harris, S., Mav, D., Shah, R., et al. (2012). Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Molecular Cell, 46(4), 424–435.PubMedCrossRefGoogle Scholar
  44. 44.
    Pleasance, E. D., Cheetham, R. K., Stephens, P. J., McBride, D. J., Humphray, S. J., Greenman, C. D., et al. (2011). A comprehensive catalogue of somatic mutations from a human cancer genome. Nature, 463(7278), 191–196.CrossRefGoogle Scholar
  45. 45.
    TCGA. (2012). Comprehensive molecular portraits of human breast tumours. Nature, 490(7418), 61–70.CrossRefGoogle Scholar
  46. 46.
    Durkin, S. G., & Glover, T. W. (2007). Chromosome fragile sites. Annual Review of Genetics, 41, 169–192.PubMedCrossRefGoogle Scholar
  47. 47.
    O’Sullivan, J. N., Bronner, M. P., Brentnall, T. A., Finley, J. C., Shen, W. T., Emerson, S., et al. (2002). Chromosomal instability in ulcerative colitis is related to telomere shortening. Nature Genetics, 32(2).Google Scholar
  48. 48.
    Stone, J. E., Lujan, S. A., & Kunkel, T. A. (2012). DNA polymerase zeta generates clustered mutations during bypass of endogenous DNA lesions in Saccharomyces cerevisiae. Environmental and Molecular Mutagenesis, 53(9), 777–786.PubMedCrossRefGoogle Scholar
  49. 49.
    Bodmer, W. (2008). Genetic instability is not a requirement for tumor development. Cancer Research, 68(10), 3558–3560.PubMedCrossRefGoogle Scholar
  50. 50.
    Beckman, R. A., & Loeb, L. A. (2005). Negative clonal selection in tumor evolution. Genetics, 171(4), 2123–2131.PubMedCrossRefGoogle Scholar
  51. 51.
    Loh, E., Salk, J. J., & Loeb, L. A. (2010). Optimization of DNA polymerase mutation rates during bacterial evolution. Proceedings of the National Academy of Sciences of the United States of America, 107(3), 1154–1159.PubMedCrossRefGoogle Scholar
  52. 52.
    Li, R., Sonik, A., Stindl, R., Rasnick, D., & Duesberg, P. (2000). Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proceedings of the National Academy of Sciences of the United States of America, 97(7), 3236–3241.PubMedCrossRefGoogle Scholar
  53. 53.
    Mitelman, F., Mark, J., Levan, G., & Levan, A. (1972). Tumor etiology and chromosome pattern. Science, 176(41), 1340–1341.PubMedCrossRefGoogle Scholar
  54. 54.
    Roylance, R., Endesfelder, D., Gorman, P., Burrell, R. A., Sander, J., Tomlinson, I., et al. (2011). Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 20(10), 2183–2194.CrossRefGoogle Scholar
  55. 55.
    Bozic, I., Antal, T., Ohtsuki, H., Carter, H., Kim, D., Chen, S., et al. (2010). Accumulation of driver and passenger mutations during tumor progression. Proceedings of the National Academy of Sciences of the United States of America, 107(43), 18545–18550.PubMedCrossRefGoogle Scholar
  56. 56.
    Bielas, J., & Loeb, L. (2005). Quantification of random genomic mutations. Natural Methology, 2(4), 285–290.CrossRefGoogle Scholar
  57. 57.
    Klein, C. A. (2008). The direct molecular analysis of metastatic precursor cells in breast cancer: a chance for a better understanding of metastasis and for personalised medicine. European Journal of Cancer, 44(18), 2721–2725.PubMedCrossRefGoogle Scholar
  58. 58.
    Wicha, M. S., Liu, S., & Dontu, G. (2006). Cancer stem cells: an old idea—a paradigm shift. Cancer Research, 66, 1883–1890.PubMedCrossRefGoogle Scholar
  59. 59.
    Cervantes, R. B., Stringer, J. R., Shao, C., Tischfield, J. A., & Stambrook, P. J. (2002). Embryonic stem cells and somatic cells differ in mutation frequency and type. Proceedings of the National Academy of Sciences of the United States of America, 99, 3586–3590.PubMedCrossRefGoogle Scholar
  60. 60.
    Yoshida, R., Miyashita, K., Inoue, M., Shimamoto, A., Yan, Z., Egashira, A., et al. (2011). Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer. European journal of human genetics: EJHG, 19(3), 320–325.PubMedCrossRefGoogle Scholar
  61. 61.
    TCGA. (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487(7407), 330–337.CrossRefGoogle Scholar
  62. 62.
    Putnam, C. D., Allen-Soltero, S. R., Martinez, S. L., Chan, J. E., Hayes, T. K., & Kolodner, R. D. (2012). Bioinformatic identification of genes suppressing genome instability. Proceedings of the National Academy of Sciences of the United States of America, 109(47), E3251–E3259.PubMedCrossRefGoogle Scholar
  63. 63.
    Levine, A. J., Momand, J., & Finlay, C. A. (1991). The P53 tumour suppressor gene. Nature, 351, 453–456.PubMedCrossRefGoogle Scholar
  64. 64.
    Liu, P. K., Kraus, E., Wu, T. A., Strong, L. C., & Tainsky, M. A. (1996). Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations. Oncogene, 12(11), 2267–2278.PubMedGoogle Scholar
  65. 65.
    Mekeel, K. L., Tang, W., Kachnic, L. A., Luo, C. M., DeFrank, J. S., & Powell, S. N. (1997). Inactivation of p53 results in high rates of homologous recombination. Oncogene, 14(15), 1847–1857.PubMedCrossRefGoogle Scholar
  66. 66.
    Schmitt, M. W., Kennedy, S. R., Salk, J. J., Fox, E. J., Hiatt, J. B., & Loeb, L. A. (2012). Detection of ultra-rare mutations by next-generation sequencing. Proceedings of the National Academy of Sciences of the United States of America, 109(36), 14508–14513.PubMedCrossRefGoogle Scholar
  67. 67.
    Shendure, J., & Ji, H. (2008). Next-generation DNA sequencing. Nature Biotechnology, 26(10), 1135–1145.PubMedCrossRefGoogle Scholar
  68. 68.
    Bielas, J. H., Loeb, K. R., Rubin, B. P., True, L. D., & Loeb, L. A. (2006). Human cancers express a mutator phenotype. Proceedings of the National Academy of Sciences of the United States of America, 103(48), 18238–18242.PubMedCrossRefGoogle Scholar
  69. 69.
    Wright, J. H., Modjeski, K. L., Bielas, J. H., Preston, B. D., Fausto, N., Loeb, L. A., et al. (2011). A random mutation capture assay to detect genomic point mutations in mouse tissue. Nucleic Acids Research, 39(11), wwe73.CrossRefGoogle Scholar
  70. 70.
    Zheng, L., Dai, H., Zhou, M., Li, M., Singh, P., Qiu, J., et al. (2007). Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nature Medicine, 13(7), 812–819.PubMedCrossRefGoogle Scholar
  71. 71.
    Radich, J. P. (2012). Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia. Cancer, 118(2), 300–311.PubMedCrossRefGoogle Scholar
  72. 72.
    Diaz, L. A., Jr., Williams, R. T., Wu, J., Kinde, I., Hecht, J. R., Berlin, J., et al. (2012). The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature, 486(7404), 537–540.PubMedGoogle Scholar
  73. 73.
    Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., Liska, D., et al. (2012). Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature, 486(7404), 532–536.PubMedGoogle Scholar
  74. 74.
    Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., et al. (2010). Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 467(7319), 1114–1117.PubMedCrossRefGoogle Scholar
  75. 75.
    Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., et al. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England Journal of Medicine, 366(10), 883–892.PubMedCrossRefGoogle Scholar
  76. 76.
    Loeb, L. A., Essigmann, J. M., Kazazi, F., Zhang, J., Rose, K. D., & Mullins, J. I. (1999). Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proceedings of the National Academy of Sciences of the United States of America, 96(4), 1492–1497.PubMedCrossRefGoogle Scholar
  77. 77.
    Grande-Perez, A., Lazaro, E., Lowenstein, P., Domingo, E., & Manrubia, S. C. (2005). Suppression of viral infectivity through lethal defection. Proceedings of the National Academy of Sciences of the United States of America, 102(12), 4448–4452.PubMedCrossRefGoogle Scholar
  78. 78.
    Eigen, M. (1993). Viral quasispecies. Scientific American, 269(1), 42–49.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Edward J. Fox
    • 1
  • Marc J. Prindle
    • 1
  • Lawrence A. Loeb
    • 1
    • 2
    Email author
  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA
  2. 2.Department of BiochemistryUniversity of WashingtonSeattleUSA

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