Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The causes and consequences of genetic heterogeneity in cancer evolution

Abstract

Recent studies have revealed extensive genetic diversity both between and within tumours. This heterogeneity affects key cancer pathways, driving phenotypic variation, and poses a significant challenge to personalized cancer medicine. A major cause of genetic heterogeneity in cancer is genomic instability. This instability leads to an increased mutation rate and can shape the evolution of the cancer genome through a plethora of mechanisms. By understanding these mechanisms we can gain insight into the common pathways of tumour evolution that could support the development of future therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intertumour and intratumour heterogeneity.

Similar content being viewed by others

References

  1. Landau, D. A. et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152, 714–726 (2013). This article examines how subclonal driver mutations influence outcome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011). An article demonstrates branched cancer evolution and genetic heterogeneity between leukaemia-propagating cells in ALL.

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cahill, D. P., Kinzler, K. W., Vogelstein, B. & Lengauer, C. Genetic instability and Darwinian selection in tumours. Trends Biochem. Sci. 24, M57–M60 (1999). An early reference placing genomic instability within the framework of Darwinian evolution, and recognizing that there may be distinct genomic footprints for different instability mechanisms.

    Article  Google Scholar 

  5. Merlo, L. M., Pepper, J. W., Reid, B. J. & Maley, C. C. Cancer as an evolutionary and ecological process. Nature Rev. Cancer 6, 924–935 (2006).

    Article  CAS  Google Scholar 

  6. Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012). This article demonstrates the impact of treatment upon both tumour evolution and mutational spectra.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hunter, C. et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987–3991 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lord, C. J. & Ashworth, A. The DNA damage response and cancer therapy. Nature 481, 287–294 (2012).

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weigelt, B. & Reis-Filho, J. S. Histological and molecular types of breast cancer: is there a unifying taxonomy? Nature Rev. Clin. Oncol. 6, 718–730 (2009).

    Article  CAS  Google Scholar 

  11. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  13. Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brown, J. M. & Attardi, L. D. The role of apoptosis in cancer development and treatment response. Nature Rev. Cancer 5, 231–237 (2005).

    Article  CAS  Google Scholar 

  15. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Popat, S., Hubner, R. & Houlston, R. S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23, 609–618 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Pao, W. & Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nature Rev. Cancer 10, 760–774 (2010).

    Article  CAS  Google Scholar 

  19. Patel, J. P. et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079–1089 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jones, S. et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283–4288 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Strauss, M., Lukas, J. & Bartek, J. Unrestricted cell cycling and cancer. Nature Med. 1, 1245–1246 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Swanton, C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 72, 4875–4882 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nature Rev. Cancer 12, 323–334 (2012).

    Article  CAS  Google Scholar 

  31. Varley, K. E., Mutch, D. G., Edmonston, T. B., Goodfellow, P. J. & Mitra, R. D. Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing. Nucleic Acids Res. 37, 4603–4612 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gatenby, R. A., Gillies, R. J. & Brown, J. S. Of cancer and cave fish. Nature Rev. Cancer 11, 237–238 (2011).

    Article  CAS  Google Scholar 

  33. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    Article  ADS  CAS  PubMed  Google Scholar 

  34. Cairns, J. Mutation selection and the natural history of cancer. Nature 255, 197–200 (1975).

    Article  ADS  CAS  PubMed  Google Scholar 

  35. Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009). This article demonstrates clonal diversity between primary and metastatic sites using next-generation sequencing.

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Keats, J. J. et al. Clonal competition with alternating dominance in multiple myeloma. Blood 120, 1067–1076 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Welch, J. S. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264–278 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shah, S. P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012).

    Article  ADS  CAS  PubMed  Google Scholar 

  42. Thirlwell, C. et al. Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. Gastroenterology 138, 1441–1454 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl Acad. Sci. USA 110, 4009–4014 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu, X. et al. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482, 529–533 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Martinez, P. et al. Parallel evolution of tumor subclones mimics diversity between tumors. J. Pathol. 230, 356–364 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nature Rev. Genet. 13, 795–806 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  48. Szerlip, N. J. et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc. Natl Acad. Sci. USA 109, 3041–3046 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011). This article reports intermingled heterogeneous subclones with mutually exclusive amplification of targetable receptor tyrosine kinases.

    Article  CAS  PubMed  Google Scholar 

  50. Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl Acad. Sci. USA 107, 961–968 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. Thompson, S. L. & Compton, D. A. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188, 369–381 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Thompson, S. L. & Compton, D. A. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180, 665–672 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Torres, E. M., Williams, B. R. & Amon, A. Aneuploidy: cells losing their balance. Genetics 179, 737–746 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gordon, D. J., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nature Rev. Genet. 13, 189–203 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. Loeb, L. A. Mutator phenotype in cancer: origin and consequences. Semin. Cancer Biol. 20, 279–280 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Weaver, B. A., Silk, A. D., Montagna, C., Verdier-Pinard, P. & Cleveland, D. W. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25–36 (2007). This article describes a mouse model that illustrates the complex relationship between the level of chromosomal instability and tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  58. Liu, X. et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl Acad. Sci. USA 104, 12111–12116 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sotillo, R., Schvartzman, J. M., Socci, N. D. & Benezra, R. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464, 436–440 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Baker, D. J., Jin, F., Jeganathan, K. B. & van Deursen, J. M. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16, 475–486 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012). References 39 and 61 demonstrate how deep sequencing can be used to elucidate the evolutionary history of tumours, and develop tools to identify mutational signatures using whole-genome sequencing data; they also describe a novel highly localized mutational process, kataegis

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sieber, O. M. et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N. Engl. J. Med. 348, 791–799 (2003).

    Article  PubMed  Google Scholar 

  65. Pfeifer, G. P. et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21, 7435–7451 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Dumaz, N., Drougard, C., Sarasin, A. & Daya-Grosjean, L. Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proc. Natl Acad. Sci. USA 90, 10529–10533 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. Palles, C. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genet. 45, 136–144 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Shah, S. N., Hile, S. E. & Eckert, K. A. Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. Cancer Res. 70, 431–435 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nikolaev, S. I. et al. A single-nucleotide substitution mutator phenotype revealed by exome sequencing of human colon adenomas. Cancer Res. 72, 6279–6289 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Yang, D. et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. J. Am. Med. Assoc. 306, 1557–1565 (2011).

    Article  CAS  Google Scholar 

  71. McGranahan, N., Burrell, R. A., Endesfelder, D., Novelli, M. R. & Swanton, C. Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep. 13, 528–538 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ganem, N. J., Storchova, Z. & Pellman, D. Tetraploidy, aneuploidy and cancer. Curr. Opin. Genet. Dev. 17, 157–162 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  74. Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bakhoum, S. F., Genovese, G. & Compton, D. A. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr. Biol. 19, 1937–1942 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bakhoum, S. F., Thompson, S. L., Manning, A. L. & Compton, D. A. Genome stability is ensured by temporal control of kinetochore–microtubule dynamics. Nature Cell Biol. 11, 27–35 (2008). This article demonstrates direct attenuation of chromosomal instability in cancer cells, through overexpression of microtubule depolymerases.

    Article  PubMed  CAS  Google Scholar 

  78. Silkworth, W. T., Nardi, I. K., Scholl, L. M. & Cimini, D. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS ONE 4, e6564 (2009).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  79. Kaseda, K., McAinsh, A. D. & Cross, R. A. Dual pathway spindle assembly increases both the speed and the fidelity of mitosis. Biol. Open 1, 12–18 (2012).

    Article  PubMed  Google Scholar 

  80. Pampalona, J., Soler, D., Genescà, A. & Tusell, L. Whole chromosome loss is promoted by telomere dysfunction in primary cells. Genes Chromosomes Cancer 49, 368–378 (2010).

    CAS  Google Scholar 

  81. Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  82. Dereli-Öz, A., Versini, G. & Halazonetis, T. D. Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress. Mol. Oncol. 5, 308–314 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  84. Barlow, J. H. et al. Identification of early replicating fragile sites that contribute to genome instability. Cell 152, 620–632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Janssen, A., van der Burg, M., Szuhai, K., Kops, G. J. & Medema, R. H. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  86. Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012). References 85 and 86 highlight different mechanisms that contribute to the complex interplay between structural and numerical chromosomal instability.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Burrell, R. A. et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 494, 492–496 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gisselsson, D. Classification of chromosome segregation errors in cancer. Chromosoma 117, 511–519 (2008).

    Article  PubMed  Google Scholar 

  89. Kawabata, T. et al. Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression. Mol. Cell 41, 543–553 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chan, K. L., North, P. S. & Hickson, I. D. BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. EMBO J. 26, 3397–3409 (2007). This study provides evidence that pre-mitotic defects can result in chromosome segregation errors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  92. Gutenberg, A. et al. High chromosomal instability in brain metastases of colorectal carcinoma. Cancer Genet. Cytogenet. 198, 47–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Lee, A. J. et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 71, 1858–1870 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  95. Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Roylance, R. et al. Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 2183–2194 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  98. Carter, S. L. et al. Absolute quantification of somatic DNA alterations in human cancer. Nature Biotechnol. 30, 413–421 (2012).

    Article  CAS  Google Scholar 

  99. Galipeau, P. C. et al. 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. Proc. Natl Acad. Sci. USA 93, 7081–7084 (1996).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  100. Taylor, J. S. & Raes, J. Duplication and divergence: the evolution of new genes and old ideas. Annu. Rev. Genet. 38, 615–643 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Ishikawa, T. et al. Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Cancer Res. 63, 5564–5572 (2003).

    CAS  PubMed  Google Scholar 

  102. Birkbak, N. J. et al. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71, 3447–3452 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kops, G. J., Foltz, D. R. & Cleveland, D. W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl Acad. Sci. USA 101, 8699–8704 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nature Struct. Mol. Biol. 17, 688–695 (2010).

    Article  CAS  Google Scholar 

  105. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  107. Ma, C. X., Janetka, J. W. & Piwnica-Worms, H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol. Med. 17, 88–96 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. Inda, M. M. et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev. 24, 1731–1745 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wu, M., Pastor-Pareja, J. C. & Xu, T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463, 545–548 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kreso, A. et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339, 543–548 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

  111. Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Rev. Cancer 9, 665–674 (2009).

    Article  CAS  Google Scholar 

  112. Gascoigne, K. E. & Taylor, S. S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111–122 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Vakiani, E. et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J. Clin. Oncol. 30, 2956–2962 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen, Z. Y. et al. EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist 17, 978–985 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Diaz, L. A. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  117. Merlo, L. M. et al. A comprehensive survey of clonal diversity measures in Barrett's esophagus as biomarkers of progression to esophageal adenocarcinoma. Cancer Prev. Res. (Phila.) 3, 1388–1397 (2010). This study develops tools to quantify intratumour heterogeneity, and relates these indices to patient outcome.

    Article  Google Scholar 

  118. Solomon, D. A. et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333, 1039–1043 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  119. Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wang, J. H. Mechanisms and impacts of chromosomal translocations in cancers. Front. Med. 6, 263–274 (2012).

    Article  ADS  PubMed  Google Scholar 

  121. McBride, D. J. et al. Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes. J. Pathol. 227, 446–455 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ng, C. K. et al. The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer. J. Pathol. 226, 703–712 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Hahn, P. J. Molecular biology of double-minute chromosomes. Bioessays 15, 477–484 (1993).

    Article  CAS  PubMed  Google Scholar 

  124. Xia, F. et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc. Natl Acad. Sci. USA 98, 8644–8649 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bermejo, R., Lai, M. S. & Foiani, M. Preventing replication stress to maintain genome stability: resolving conflicts between replication and transcription. Mol. Cell 45, 710–718 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to apologize to those whose work we have not been able to cite owing to space limitations. C.S. is funded by Cancer Research UK, The Medical Research Council, EU FP7 (projects PREDICT and RESPONSIFY), Prostate Cancer Foundation and the Breast Cancer Research Foundation (BCRF). J.B. is funded by the Danish Cancer Society and the European Commission (projects DDResponse and Biomedreg). We thank E. Grönroos and P. Gorman for the use of the tumour section image in Fig. 1.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charles Swanton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burrell, R., McGranahan, N., Bartek, J. et al. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501, 338–345 (2013). https://doi.org/10.1038/nature12625

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12625

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer