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.

An evolutionary perspective on field cancerization

Key Points

  • Mutations naturally accrue and clonally expand in ageing tissues, but only a subset of these mutations increases the risk of cancer development.

  • A cancerized lineage is one that has acquired some but not all the phenotypic traits required for malignancy. Typically, this means that a cancerized lineage has a survival or growth advantage over normal cells but is incapable of growing into a tumour.

  • Field cancerization is both enabled by and causes changes to the tissue microenvironment.

  • Mutagen exposure and naturally occurring age-related mutations initiate cancerized fields.

  • Field cancerization can occur without morphological change, meaning that histopathology of a tissue alone is an inadequate biomarker of cancer risk.

  • Measurements of the evolution of the cancerized field offer promise as a new class of biomarker of cancer risk and provide a means to mechanistically assess the impact of chemoprevention strategies.

  • Longitudinally collected tissue samples from patients undergoing surveillance in tissues frequently affected by field cancerization provide an underexploited resource for the study of clonal evolution over space and time in humans.

Abstract

Tumorigenesis begins long before the growth of a clinically detectable lesion and, indeed, even before any of the usual morphological correlates of pre-malignancy are recognizable. Field cancerization, which is the replacement of the normal cell population by a cancer-primed cell population that may show no morphological change, is now recognized to underlie the development of many types of cancer, including the common carcinomas of the lung, colon, skin, prostate and bladder. Field cancerization is the consequence of the evolution of somatic cells in the body that results in cells that carry some but not all phenotypes required for malignancy. Here, we review the evidence of field cancerization across organs and examine the biological mechanisms that drive the evolutionary process that results in field creation. We discuss the clinical implications, principally, how measurements of the cancerized field could improve cancer risk prediction in patients with pre-malignant disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Characterization and initiation of a cancerized field.
Figure 2: Evolutionary trajectories of cancerized clones.
Figure 3: Morphological mechanisms and examples of clonal expansion.

References

  1. 1

    Braakhuis, B. J., Tabor, M. P., Kummer, J. A., Leemans, C. R. & Brakenhoff, R. H. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res. 63, 1727–1730 (2003). This study presents the updated concept of field cancerization, which includes a genetic perspective.

    CAS  Google Scholar 

  2. 2

    Garcia, S. B., Park, H. S., Novelli, M. & Wright, N. A. Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J. Pathol. 187, 61–81 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kaz, A. M., Grady, W. M., Stachler, M. D. & Bass, A. J. Genetic and epigenetic alterations in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterol. Clin. North Am. 44, 473–489 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. 4

    Virnig, B. A., Tuttle, T. M., Shamliyan, T. & Kane, R. L. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J. Natl Cancer Inst. 102, 170–178 (2010).

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Bostwick, D. G. & Cheng, L. Precursors of prostate cancer. Histopathology 60, 4–27 (2012).

    PubMed  Google Scholar 

  6. 6

    Prasad, G. A. et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett's esophagus. Gastroenterology 132, 1226–1233 (2007).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Nordenvall, C., Ekbom, A., Bottai, M., Smedby, K. E. & Nilsson, P. J. Mortality after total colectomy in 3084 patients with inflammatory bowel disease: a population-based cohort study. Aliment. Pharmacol. Ther. 40, 280–287 (2014).

    CAS  PubMed  Google Scholar 

  8. 8

    Laine, L. et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest. Endosc. 81, 489–501.e26 (2015).

    Google Scholar 

  9. 9

    Shaheen, N. J., Falk, G. W., Iyer, P. G. & Gerson, L. B. ACG Clinical Guideline: Diagnosis and management of Barrett's esophagus. Am. J. Gastroenterol. 111, 30–50 (2016).

    CAS  PubMed  Google Scholar 

  10. 10

    Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016). This study includes a genome-wide measurement of the accumulation of age-associated mutations in the intestine and liver.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Blanpain, C. & Simons, B. D. Unravelling stem cell dynamics by lineage tracing. Nat. Rev. Mol. Cell Biol. 14, 489–502 (2013).

    CAS  PubMed  Google Scholar 

  12. 12

    Klein, A. M., Brash, D. E., Jones, P. H. & Simons, B. D. Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia. Proc. Natl Acad. Sci. USA 107, 270–275 (2010).

    CAS  PubMed  Google Scholar 

  13. 13

    Baker, A. M. et al. Quantification of crypt and stem cell evolution in the normal and neoplastic human colon. Cell Rep. 8, 940–947 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Kim, K. M., Calabrese, P., Tavare, S. & Shibata, D. Enhanced stem cell survival in familial adenomatous polyposis. Am. J. Pathol. 164, 1369–1377 (2004).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Vortmeyer, A. O. & Alomari, A. K. Pathology of the nervous system in Von Hippel-Lindau disease. J. Kidney Cancer VHL 2, 114–129 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Slaughter, D. P., Southwick, H. W. & Smejkal, W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953). This is the original paper proposing the concept of field cancerization.

    CAS  Google Scholar 

  17. 17

    Franklin, W. A. et al. Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J. Clin. Invest. 100, 2133–2137 (1997). This study shows field cancerization in the human lung by interlobe clonal expansion of a TP53 -mutant clone.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Ushijima, T. & Hattori, N. Molecular pathways: involvement of Helicobacter pylori-triggered inflammation in the formation of an epigenetic field defect, and its usefulness as cancer risk and exposure markers. Clin. Cancer Res. 18, 923–929 (2012). This study describes epigenetic fields as a cause of field cancerization in the stomach.

    CAS  PubMed  Google Scholar 

  19. 19

    Nosho, K. et al. A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology 137, 1609–1620.e3 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Lochhead, P. et al. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod. Pathol. 28, 14–29 (2015).

    PubMed  Google Scholar 

  22. 22

    Hu, B. et al. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149, 1207–1220 (2012). This study demonstrates that field cancerization can be initiated by stromal cell changes rather than by epithelial cell changes.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Calabrese, P., Tavare, S. & Shibata, D. Pretumor progression: clonal evolution of human stem cell populations. Am. J. Pathol. 164, 1337–1346 (2004).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Greaves, M. Evolutionary determinants of cancer. Cancer Discov. 5, 806–820 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015). This study identifies an extensive amount of cancer-associated mutations in morphologically normal human skin.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Alcolea, M. P. et al. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat. Cell Biol. 16, 615–622 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Jonason, A. S. et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 93, 14025–14029 (1996).

    CAS  PubMed  Google Scholar 

  29. 29

    Sanchez-Danes, A. et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536, 298–303 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Bonilla, X. et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat. Genet. 48, 398–406 (2016).

    CAS  PubMed  Google Scholar 

  31. 31

    Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013). This study quantifies the selective advantage of pretumour mutations in the intestine.

    CAS  Google Scholar 

  32. 32

    Galandiuk, S. et al. Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis. Gastroenterology 142, 855–864.e8 (2012). This study identifies examples of field cancerization by mutant clones in human Crohn's disease.

    Google Scholar 

  33. 33

    Leedham, S. J. et al. Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology 136, 542–550.e6 (2009). This study identifies examples of field cancerization at individual crypt resolution in human colitis.

    Google Scholar 

  34. 34

    Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Kato, S., Lippman, S. M., Flaherty, K. T. & Kurzrock, R. The conundrum of genetic “drivers” in benign conditions. J. Natl Cancer Inst. 108, djw036 (2016).

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Bieging, K. T., Mello, S. S. & Attardi, L. D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 14, 359–370 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Weaver, J. M. et al. Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. Nat. Genet. 46, 837–843 (2014). This study shows the general lack of stage-specificity of genetic mutations in BE.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Li, X. et al. Temporal and spatial evolution of somatic chromosomal alterations: a case-cohort study of Barrett's esophagus. Cancer Prev. Res. 7, 114–127 (2014).

    Google Scholar 

  39. 39

    Stachler, M. D. et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat. Genet. 47, 1047–1055 (2015). This study illustrates the multiple genetic pathways, including a punctuated genome-doubling pathway, that lead from BE to oesophageal cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Curvers, W. L. et al. Low-grade dysplasia in Barrett's esophagus: overdiagnosed and underestimated. Am. J. Gastroenterol. 105, 1523–1530 (2010).

    PubMed  Google Scholar 

  41. 41

    Kerkhof, M. et al. Grading of dysplasia in Barrett's oesophagus: substantial interobserver variation between general and gastrointestinal pathologists. Histopathology 50, 920–927 (2007).

    CAS  PubMed  Google Scholar 

  42. 42

    Tomasetti, C., Li, L. & Vogelstein, B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017). This study suggests a critical role for pretumour mutation accumulation in cancer development.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015). This study identifies mutational processes that underlie age-associated mutation accumulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Steiling, K., Ryan, J., Brody, J. S. & Spira, A. The field of tissue injury in the lung and airway. Cancer Prev. Res. 1, 396–403 (2008).

    CAS  Google Scholar 

  47. 47

    Burd, E. M. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 16, 1–17 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Yakirevich, E. & Resnick, M. B. Pathology of gastric cancer and its precursor lesions. Gastroenterol. Clin. North Am. 42, 261–284 (2013).

    Google Scholar 

  49. 49

    Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).

    CAS  Google Scholar 

  50. 50

    Rubenstein, J. H. & Taylor, J. B. Meta-analysis: the association of oesophageal adenocarcinoma with symptoms of gastro-oesophageal reflux. Aliment. Pharmacol. Ther. 32, 1222–1227 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Dulak, A. M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478–486 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Tomasetti, C., Vogelstein, B. & Parmigiani, G. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc. Natl Acad. Sci. USA 110, 1999–2004 (2013). This study suggests that most somatic mutations in cancer accrue prior to the initiation of cancer growth.

    CAS  PubMed  Google Scholar 

  53. 53

    Robles, A. I. et al. Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology 150, 931–943 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Issa, J. P., Ahuja, N., Toyota, M., Bronner, M. P. & Brentnall, T. A. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 61, 3573–3577 (2001).

    CAS  Google Scholar 

  55. 55

    Risques, R. A. et al. Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology 135, 410–418 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Curtius, K. et al. A molecular clock infers heterogeneous tissue age among patients with Barrett's esophagus. PLoS Comput. Biol. 12, e1004919 (2016).

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

    CAS  Google Scholar 

  58. 58

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

    CAS  PubMed  Google Scholar 

  59. 59

    Lin, J. et al. Polyclonality of BRAF mutations in acquired melanocytic nevi. J. Natl Cancer Inst. 101, 1423–1427 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Halberg, R. B. & Dove, W. F. Polyclonal tumors in the mammalian intestine: are interactions among multiple initiated clones necessary for tumor initiation, growth, and progression? Cell Cycle 6, 44–51 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Bjerknes, M. & Cheng, H. Colossal crypts bordering colon adenomas in ApcMin mice express full-length Apc. Am. J. Pathol. 154, 1831–1834 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Thliveris, A. T. et al. Polyclonality of familial murine adenomas: analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions. Proc. Natl Acad. Sci. USA 102, 6960–6965 (2005).

    CAS  PubMed  Google Scholar 

  63. 63

    Fernandez-Sanchez, M. E. et al. Mechanical induction of the tumorigenic beta-catenin pathway by tumour growth pressure. Nature 523, 92–95 (2015).

    CAS  PubMed  Google Scholar 

  64. 64

    Martens, E. A., Kostadinov, R., Maley, C. C. & Hallatschek, O. Spatial structure increases the waiting time for cancer. New J. Phys. 13, 115014 (2011).

    PubMed  PubMed Central  Google Scholar 

  65. 65

    Greaves, L. C. et al. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc. Natl Acad. Sci. USA 103, 714–719 (2006).

    CAS  Google Scholar 

  66. 66

    McDonald, S. A. et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134, 500–510 (2008). This study provides a genetic demonstration of field cancerization in the human stomach.

    CAS  PubMed  Google Scholar 

  67. 67

    Nicholson, A. M. et al. Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut 61, 1380–1389 (2012).

    CAS  PubMed  Google Scholar 

  68. 68

    Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).

    CAS  PubMed  Google Scholar 

  69. 69

    Doupe, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Teixeira, V. H. et al. Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors. eLife 2, e00966 (2013).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Nystul, T. & Spradling, A. An epithelial niche in the Drosophila ovary undergoes long-range stem cell replacement. Cell Stem Cell 1, 277–285 (2007).

    CAS  Google Scholar 

  72. 72

    Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).

    CAS  Google Scholar 

  73. 73

    Frieda, K. L. et al. Synthetic recording and in situ readout of lineage information in single cells. Nature 541, 107–111 (2017).

    CAS  PubMed  Google Scholar 

  74. 74

    McKenna, A. et al. Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353, aaf7907 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Snippert, H. J., Schepers, A. G., van Es, J. H., Simons, B. D. & Clevers, H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 15, 62–69 (2014).

    CAS  Google Scholar 

  76. 76

    Choi, C. R., Bakir, I. A., Hart, A. L. & Graham, T. A. Clonal evolution of colorectal cancer in IBD. Nat. Rev. Gastroenterol. Hepatol. 14, 218–229 (2017).

    PubMed  Google Scholar 

  77. 77

    Reid, B. J., Li, X., Galipeau, P. C. & Vaughan, T. L. Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat. Rev. Cancer 10, 87–101 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Hazelton, W. D. et al. The role of gastroesophageal reflux and other factors during progression to esophageal adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 24, 1012–1023 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Korolev, K. S., Xavier, J. B. & Gore, J. Turning ecology and evolution against cancer. Nat. Rev. Cancer 14, 371–380 (2014).

    CAS  PubMed  Google Scholar 

  80. 80

    Martincorena, I., Jones, P. H. & Campbell, P. J. Constrained positive selection on cancer mutations in normal skin. Proc. Natl Acad. Sci. USA 113, E1128–E1129 (2016).

    CAS  PubMed  Google Scholar 

  81. 81

    Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    CAS  Google Scholar 

  82. 82

    Davis, H. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 21, 62–70 (2015).

    CAS  PubMed  Google Scholar 

  83. 83

    Rutter, M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451–459 (2004).

    Google Scholar 

  84. 84

    Saadi, A. et al. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc. Natl Acad. Sci. USA 107, 2177–2182 (2010). This study shows consistent changes in the gene expression profile of cells within the stromal compartment across pre-malignant gastrointestinal diseases.

    CAS  PubMed  Google Scholar 

  85. 85

    Bronisz, A. et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat. Cell Biol. 14, 159–167 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Tomlinson, I. P. et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet. 7, e1002105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    CAS  Google Scholar 

  89. 89

    Gatenby, R. A. & Gillies, R. J. A microenvironmental model of carcinogenesis. Nat. Rev. Cancer 8, 56–61 (2008). This perspective proposes critical microenvironmental barriers that must be overcome during tumorigenesis.

    CAS  Google Scholar 

  90. 90

    Perez-Mancera, P. A., Young, A. R. & Narita, M. Inside and out: the activities of senescence in cancer. Nat. Rev. Cancer 14, 547–558 (2014).

    CAS  Google Scholar 

  91. 91

    Welch, H. G. & Black, W. C. Overdiagnosis in cancer. J. Natl Cancer Inst. 102, 605–613 (2010).

    Google Scholar 

  92. 92

    Mori, H. et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc. Natl Acad. Sci. USA 99, 8242–8247 (2002).

    CAS  Google Scholar 

  93. 93

    Greaves, M. F., Maia, A. T., Wiemels, J. L. & Ford, A. M. Leukemia in twins: lessons in natural history. Blood 102, 2321–2333 (2003).

    CAS  Google Scholar 

  94. 94

    Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014). This study shows how the mutation burden in ostensibly normal white blood cells confers leukaemia risk.

    PubMed  PubMed Central  Google Scholar 

  95. 95

    Hvid-Jensen, F., Pedersen, L., Drewes, A. M., Sorensen, H. T. & Funch-Jensen, P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N. Engl. J. Med. 365, 1375–1383 (2011).

    CAS  Google Scholar 

  96. 96

    Spechler, S. J. Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA 310, 627–636 (2013).

    CAS  PubMed  Google Scholar 

  97. 97

    Greaves, M. Does everyone develop covert cancer? Nat. Rev. Cancer 14, 209–210 (2014). This commentary elegantly discusses the inevitably of cancerization.

    CAS  PubMed  Google Scholar 

  98. 98

    Runge, T. M., Abrams, J. A. & Shaheen, N. J. Epidemiology of Barrett's esophagus and esophageal adenocarcinoma. Gastroenterol. Clin. North Am. 44, 203–231 (2015).

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Odze, R. D. Diagnosis and grading of dysplasia in Barrett's oesophagus. J. Clin. Pathol. 59, 1029–1038 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Choi, C. H. et al. Forty-year analysis of colonoscopic surveillance for neoplasia in ulcerative colitis: an updated overview. Am. J. Gastroenterol. 110, 1022–1034 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. 101

    Bird-Lieberman, E. L. et al. Population-based study reveals new risk-stratification biomarker panel for Barrett's esophagus. Gastroenterology 143, 927–935.e3 (2012).

    CAS  PubMed  Google Scholar 

  102. 102

    Reid, B. J. et al. Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am. J. Gastroenterol. 96, 2839–2848 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Timmer, M. R. et al. Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study. Gut 65, 1602–1610 (2016).

    CAS  PubMed  Google Scholar 

  104. 104

    Silvestri, G. A. et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N. Engl. J. Med. 373, 243–251 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Spira, A. et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat. Med. 13, 361–366 (2007).

    CAS  PubMed  Google Scholar 

  106. 106

    Dhawan, A., Graham, T. A. & Fletcher, A. G. A. Computational modeling approach for deriving biomarkers to predict cancer risk in premalignant disease. Cancer Prev. Res. 9, 283–295 (2016).

    CAS  Google Scholar 

  107. 107

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

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Maley, C. C. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat. Genet. 38, 468–473 (2006). This study shows how measurement of the cancerized field — in this case, the evolvability as measured by genetic diversity — predicts future cancer risk.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Martinez, P. et al. Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus. Nat. Commun. 7, 12158 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Andor, N. et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat. Med. 22, 105–113 (2016).

    CAS  Google Scholar 

  111. 111

    Maley, C. C. et al. The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res. 64, 7629–7633 (2004).

    CAS  PubMed  Google Scholar 

  112. 112

    Willenbucher, R. F. 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  PubMed Central  Google Scholar 

  113. 113

    Salk, J. J. et al. Clonal expansions in ulcerative colitis identify patients with neoplasia. Proc. Natl Acad. Sci. USA 106, 20871–20876 (2009). This study demonstrates that evidence of recent clonal expansion in patients with colitis indicates increased cancer risk.

    CAS  Google Scholar 

  114. 114

    Curtius, K., Hazelton, W. D., Jeon, J. & Luebeck, E. G. A. Multiscale model evaluates screening for neoplasia in Barrett's esophagus. PLoS Comput. Biol. 11, e1004272 (2015). This study demonstrates how computational modelling of field cancerization can help optimize screening protocols.

    PubMed  PubMed Central  Google Scholar 

  115. 115

    de Koning, H. J. et al. Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force. Ann. Intern. Med. 160, 311–320 (2014).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Hanin, L. & Pavlova, L. Optimal screening schedules for prevention of metastatic cancer. Stat. Med. 32, 206–219 (2013).

    PubMed  Google Scholar 

  117. 117

    Jeon, J., Meza, R., Moolgavkar, S. H. & Luebeck, E. G. Evaluation of screening strategies for pre-malignant lesions using a biomathematical approach. Math. Biosci. 213, 56–70 (2008).

    PubMed  PubMed Central  Google Scholar 

  118. 118

    Kong, C. Y. et al. Exploring the recent trend in esophageal adenocarcinoma incidence and mortality using comparative simulation modeling. Cancer Epidemiol. Biomarkers Prev. 23, 997–1006 (2014).

    PubMed  PubMed Central  Google Scholar 

  119. 119

    Ryser, M. D., Lee, W. T., Ready, N. E., Leder, K. Z. & Foo, J. Quantifying the dynamics of field cancerization in tobacco-related head and neck cancer: a multiscale modeling approach. Cancer Res. 76, 7078–7088 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Galipeau, P. C. et al. NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med. 4, e67 (2007).

    PubMed  PubMed Central  Google Scholar 

  121. 121

    Kostadinov, R. L. et al. NSAIDs modulate clonal evolution in Barrett's esophagus. PLoS Genet. 9, e1003553 (2013). This study suggests that NSAIDs reduce cancer risk by inhibiting clonal evolution within a cancerized field in BE.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Zhao, L. N. et al. 5-Aminosalicylates reduce the risk of colorectal neoplasia in patients with ulcerative colitis: an updated meta-analysis. PLoS ONE 9, e94208 (2014).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Rothwell, P. M. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377, 31–41 (2011).

    CAS  Google Scholar 

  124. 124

    Hvid-Jensen, F., Pedersen, L., Funch-Jensen, P. & Drewes, A. M. Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett's oesophagus: a nationwide study of 9883 patients. Aliment. Pharmacol. Ther. 39, 984–991 (2014).

    CAS  PubMed  Google Scholar 

  125. 125

    Gee, J., Sabichi, A. L. & Grossman, H. B. Chemoprevention of superficial bladder cancer. Crit. Rev. Oncol. Hematol. 43, 277–286 (2002).

    PubMed  Google Scholar 

  126. 126

    Herr, H. W. et al. Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J. Clin. Oncol. 13, 1404–1408 (1995).

    CAS  PubMed  Google Scholar 

  127. 127

    Lamm, D. L. et al. Maintenance Bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J. Urol. 163, 1124–1129 (2000).

    CAS  Google Scholar 

  128. 128

    Redelman-Sidi, G., Glickman, M. S. & Bochner, B. H. The mechanism of action of BCG therapy for bladder cancer — a current perspective. Nat. Rev. Urol. 11, 153–162 (2014).

    CAS  PubMed  Google Scholar 

  129. 129

    Foo, J., Leder, K. & Ryser, M. D. Multifocality and recurrence risk: a quantitative model of field cancerization. J. Theor. Biol. 355, 170–184 (2014).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    Gupta, M. et al. Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium. Gastroenterology 145, 79–86.e1 (2013).

    PubMed  PubMed Central  Google Scholar 

  131. 131

    Rutgeerts, P. et al. Predictability of the postoperative course of Crohn's disease. Gastroenterology 99, 956–963 (1990).

    CAS  Google Scholar 

  132. 132

    Choi, C. H. et al. Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer. Am. J. Gastroenterol. 110, 1461–1471 (2015).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Morrow, M. et al. Society of Surgical Oncology–American Society for Radiation Oncology–American Society of Clinical Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. Ann. Surg. Oncol. 23, 3801–3810 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. 134

    Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 46, 176–181 (2014).

    CAS  Google Scholar 

  135. 135

    Esserman, L. J. et al. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol. 15, e234–e242 (2014). This article highlights the current scale of the overdiagnosis and overtreatment problem in pre-malignant disease.

    PubMed  PubMed Central  Google Scholar 

  136. 136

    Campbell, J. D. et al. The case for a Pre-Cancer Genome Atlas (PCGA). Cancer Prev. Res. 9, 119–124 (2016).

    CAS  Google Scholar 

  137. 137

    Koizumi, K. et al. Array-based identification of common DNA methylation alterations in ulcerative colitis. Int. J. Oncol. 40, 983–994 (2012).

    CAS  PubMed  Google Scholar 

  138. 138

    van Dekken, H. et al. Genomic analysis of a case of multifocal adenocarcinoma in ulcerative colitis. Virchows Arch. 449, 716–721 (2006).

    PubMed  Google Scholar 

  139. 139

    Alonso, S. et al. Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans. Oncotarget 6, 3420–3431 (2015).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Asada, K. et al. FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect. Oncogene 32, 2140–2149 (2013).

    CAS  PubMed  Google Scholar 

  141. 141

    Damania, D. et al. Nanocytology of rectal colonocytes to assess risk of colon cancer based on field cancerization. Cancer Res. 72, 2720–2727 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Hawthorn, L., Lan, L. & Mojica, W. Evidence for field effect cancerization in colorectal cancer. Genomics 103, 211–221 (2014).

    CAS  Google Scholar 

  143. 143

    Kamiyama, H. et al. DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene 31, 5029–5037 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Kaz, A. M. et al. Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age. Epigenetics 9, 492–502 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Milicic, A. et al. Ectopic expression of P-cadherin correlates with promoter hypomethylation early in colorectal carcinogenesis and enhanced intestinal crypt fission in vivo. Cancer Res. 68, 7760–7768 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Shen, L. et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J. Natl Cancer Inst. 97, 1330–1338 (2005).

    CAS  PubMed  Google Scholar 

  147. 147

    Gutierrez-Gonzalez, L. et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 140, 1251–1260.e6 (2011).

    CAS  PubMed  Google Scholar 

  148. 148

    Kang, G. H. et al. Genetic evidence for the multicentric origin of synchronous multiple gastric carcinoma. Lab. Invest. 76, 407–417 (1997).

    CAS  PubMed  Google Scholar 

  149. 149

    Takeshima, H. et al. Frequent involvement of chromatin remodeler alterations in gastric field cancerization. Cancer Lett. 357, 328–338 (2015).

    CAS  PubMed  Google Scholar 

  150. 150

    Yamanoi, K. et al. Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome. Carcinogenesis 36, 509–520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Zaky, A. H. et al. Clinicopathologic implications of genetic instability in intestinal-type gastric cancer and intestinal metaplasia as a precancerous lesion: proof of field cancerization in the stomach. Am. J. Clin. Pathol. 129, 613–621 (2008).

    PubMed  Google Scholar 

  152. 152

    Cense, H. A., van Lanschot, J. J., Fockens, P., Obertop, H. & Offerhaus, G. J. A patient with seven primary tumors of the upper aerodigestive tract: the process of field cancerization versus distant monoclonal expansion. Dis. Esophagus 10, 139–142 (1997).

    CAS  PubMed  Google Scholar 

  153. 153

    Kammori, M. et al. Squamous cell carcinomas of the esophagus arise from a telomere-shortened epithelial field. Int. J. Mol. Med. 20, 793–799 (2007).

    CAS  PubMed  Google Scholar 

  154. 154

    Lee, Y. C. et al. Revisit of field cancerization in squamous cell carcinoma of upper aerodigestive tract: better risk assessment with epigenetic markers. Cancer Prev. Res. 4, 1982–1992 (2011).

    CAS  Google Scholar 

  155. 155

    Matsuda, Y. et al. Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization. Cancer Causes Control 23, 865–873 (2012).

    PubMed  Google Scholar 

  156. 156

    Oka, D. et al. The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking history: a target for risk diagnosis and prevention of esophageal cancers. Cancer 115, 3412–3426 (2009).

    CAS  PubMed  Google Scholar 

  157. 157

    Roesch-Ely, M. et al. Proteomic analysis of field cancerization in pharynx and oesophagus: a prospective pilot study. J. Pathol. 221, 462–470 (2010).

    PubMed  Google Scholar 

  158. 158

    Yakoub, D., Keun, H. C., Goldin, R. & Hanna, G. B. Metabolic profiling detects field effects in nondysplastic tissue from esophageal cancer patients. Cancer Res. 70, 9129–9136 (2010).

    CAS  PubMed  Google Scholar 

  159. 159

    Galipeau, P. C., Prevo, L. J., Sanchez, C. A., Longton, G. M. & Reid, B. J. Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue. J. Natl Cancer Inst. 91, 2087–2095 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Maley, C. C. et al. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus. Cancer Res. 64, 3414–3427 (2004).

    CAS  PubMed  Google Scholar 

  161. 161

    van Dekken, H., Vissers, C. J., Tilanus, H. W., Tanke, H. J. & Rosenberg, C. Clonal analysis of a case of multifocal oesophageal (Barrett's) adenocarcinoma by comparative genomic hybridization. J. Pathol. 188, 263–266 (1999).

    CAS  PubMed  Google Scholar 

  162. 162

    Chang, Y. L. et al. Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers. Clin. Cancer Res. 13, 52–58 (2007).

    CAS  PubMed  Google Scholar 

  163. 163

    Kadara, H. & Wistuba, I. I. Field cancerization in non-small cell lung cancer: implications in disease pathogenesis. Proc. Am. Thorac Soc. 9, 38–42 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    McCaughan, F. et al. Genomic evidence of pre-invasive clonal expansion, dispersal and progression in bronchial dysplasia. J. Pathol. 224, 153–159 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Pipinikas, C. P. et al. Cell migration leads to spatially distinct but clonally related airway cancer precursors. Thorax 69, 548–557 (2014).

    PubMed  PubMed Central  Google Scholar 

  166. 166

    Sozzi, G. et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 55, 135–140 (1995).

    CAS  PubMed  Google Scholar 

  167. 167

    Gomperts, B. N., Walser, T. C., Spira, A. & Dubinett, S. M. Enriching the molecular definition of the airway “field of cancerization:” establishing new paradigms for the patient at risk for lung cancer. Cancer Prev. Res. 6, 4–7 (2013).

    CAS  Google Scholar 

  168. 168

    Kadara, H. et al. Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. J. Natl Cancer Inst. 106, dju004 (2014).

    PubMed  PubMed Central  Google Scholar 

  169. 169

    Lin, M. W., Wu, C. T., Kuo, S. W., Chang, Y. L. & Yang, P. C. Clinicopathology and genetic profile of synchronous multiple small adenocarcinomas: implication for surgical treatment of an uncommon lung malignancy. Ann. Surg. Oncol. 21, 2555–2562 (2014).

    PubMed  Google Scholar 

  170. 170

    Nakachi, I. et al. Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions. Cancer Prev. Res. 7, 255–265 (2014).

    CAS  Google Scholar 

  171. 171

    Weichert, W. & Warth, A. Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Curr. Opin. Pulm. Med. 20, 309–316 (2014).

    CAS  PubMed  Google Scholar 

  172. 172

    Wirtschafter, E., Walts, A. E., Liu, S. T. & Marchevsky, A. M. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia of the lung (DIPNECH): current best evidence. Lung 193, 659–667 (2015).

    CAS  PubMed  Google Scholar 

  173. 173

    Angadi, P. V., Savitha, J. K., Rao, S. S. & Sivaranjini, Y. Oral field cancerization: current evidence and future perspectives. Oral Maxillofac. Surg. 16, 171–180 (2012).

    PubMed  Google Scholar 

  174. 174

    Boscolo-Rizzo, P. et al. Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma. Oral Oncol. 51, 500–507 (2015).

    CAS  PubMed  Google Scholar 

  175. 175

    Califano, J. et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 56, 2488–2492 (1996).

    CAS  PubMed  Google Scholar 

  176. 176

    Narayana, A., Vaughan, A. T., Fisher, S. G. & Reddy, S. P. Second primary tumors in laryngeal cancer: results of long-term follow-up. Int. J. Radiat. Oncol. Biol. Phys. 42, 557–562 (1998).

    CAS  PubMed  Google Scholar 

  177. 177

    Pentenero, M. et al. Field effect in oral precancer as assessed by DNA flow cytometry and array-CGH. J. Oral Pathol. Med. 41, 119–123 (2012).

    CAS  PubMed  Google Scholar 

  178. 178

    Shaw, R. J. et al. Molecular staging of surgical margins in oral squamous cell carcinoma using promoter methylation of p16INK4A, cytoglobin, E-cadherin, and TMEFF2. Ann. Surg. Oncol. 20, 2796–2802 (2013).

    PubMed  Google Scholar 

  179. 179

    Van der Vorst, S., Dekairelle, A. F., Weynand, B., Hamoir, M. & Gala, J. L. Assessment of p53 functional activity in tumor cells and histologically normal mucosa from patients with head and neck squamous cell carcinoma. Head Neck 34, 1542–1550 (2012).

    PubMed  Google Scholar 

  180. 180

    Dworkin, A. M., Huang, T. H. & Toland, A. E. Epigenetic alterations in the breast: Implications for breast cancer detection, prognosis and treatment. Semin. Cancer Biol. 19, 165–171 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    Ellsworth, D. L. et al. Outer breast quadrants demonstrate increased levels of genomic instability. Ann. Surg. Oncol. 11, 861–868 (2004).

    PubMed  Google Scholar 

  182. 182

    Foschini, M. P. et al. Genetic clonal mapping of in situ and invasive ductal carcinoma indicates the field cancerization phenomenon in the breast. Hum. Pathol. 44, 1310–1319 (2013).

    CAS  PubMed  Google Scholar 

  183. 183

    Rivenbark, A. G. & Coleman, W. B. Field cancerization in mammary carcinogenesis - Implications for prevention and treatment of breast cancer. Exp. Mol. Pathol. 93, 391–398 (2012).

    CAS  Google Scholar 

  184. 184

    Trujillo, K. A. et al. Breast field cancerization: isolation and comparison of telomerase-expressing cells in tumor and tumor adjacent, histologically normal breast tissue. Mol. Cancer Res. 9, 1209–1221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Haaland, C. M. et al. Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization. Int. J. Oncol. 35, 537–546 (2009).

    CAS  PubMed  Google Scholar 

  186. 186

    Nonn, L., Ananthanarayanan, V. & Gann, P. H. Evidence for field cancerization of the prostate. Prostate 69, 1470–1479 (2009).

    PubMed  PubMed Central  Google Scholar 

  187. 187

    Trujillo, K. A., Jones, A. C., Griffith, J. K. & Bisoffi, M. Markers of field cancerization: proposed clinical applications in prostate biopsies. Prostate Cancer 2012, 302894 (2012).

    PubMed  PubMed Central  Google Scholar 

  188. 188

    Hafner, C., Knuechel, R., Stoehr, R. & Hartmann, A. Clonality of multifocal urothelial carcinomas: 10 years of molecular genetic studies. Int. J. Cancer 101, 1–6 (2002).

    CAS  PubMed  Google Scholar 

  189. 189

    Vriesema, J. L., Aben, K. K., Witjes, J. A., Kiemeney, L. A. & Schalken, J. A. Superficial and metachronous invasive bladder carcinomas are clonally related. Int. J. Cancer 93, 699–702 (2001).

    CAS  PubMed  Google Scholar 

  190. 190

    Wang, Y., Lang, M. R., Pin, C. L. & Izawa, J. I. Comparison of the clonality of urothelial carcinoma developing in the upper urinary tract and those developing in the bladder. SpringerPlus 2, 412 (2013).

    PubMed  PubMed Central  Google Scholar 

  191. 191

    Kanjilal, S. et al. p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization. Cancer Res. 55, 3604–3609 (1995).

    CAS  PubMed  Google Scholar 

  192. 192

    Stern, R. S., Bolshakov, S., Nataraj, A. J. & Ananthaswamy, H. N. p53 mutation in nonmelanoma skin cancers occurring in psoralen ultraviolet a-treated patients: evidence for heterogeneity and field cancerization. J. Invest. Dermatol. 119, 522–526 (2002).

    CAS  PubMed  Google Scholar 

  193. 193

    Szeimies, R. M. et al. Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy. Br. J. Dermatol. 167, 150–159 (2012).

    CAS  PubMed  Google Scholar 

  194. 194

    Vatve, M., Ortonne, J. P., Birch-Machin, M. A. & Gupta, G. Management of field change in actinic keratosis. Br. J. Dermatol. 157 (Suppl. 2), 21–24 (2007).

    CAS  PubMed  Google Scholar 

  195. 195

    Shain, A. H. et al. The genetic evolution of melanoma from precursor lesions. N. Engl. J. Med. 373, 1926–1936 (2015).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank D. Brash for helpful conversations during the writing of this manuscript. The authors acknowledge funding from Cancer Research UK (grants A19771 to T.A.G. and A21870 to N.A.W.), the Wellcome Trust (202778/Z/16/Z to T.A.G.) and the Barts Charity (472–2300 to K.C. and T.A.G.).

Author information

Affiliations

Authors

Contributions

All authors researched data for the article, made substantial contributions to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Trevor A. Graham.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Cell lineage

A group of cells that share a recent common ancestor cell; also known as a clone.

Epimutations

Gains or losses of DNA methylation or heritable chromatin changes; such changes are in contrast to genetic changes to DNA nucleotides.

Cancerized field

A collection of cells that have gained some but not all the phenotypic alterations required for malignancy; in general, the altered phenotype will have been caused by an underlying mutation.

Dysplasia

A feature of tissues in which cells have an abnormal morphology or arrangement, usually regarded as being an unequivocal neoplastic alteration.

Hyperplasia

A feature of tissues in which an increase in cell number occurs without malignant change.

Metaplasia

A feature of tissues in which the usual cells of a tissue are replaced with a cell type that morphologically resembles another tissue type.

Inflammatory bowel disease

(IBD). A group of inflammatory conditions of the bowel that includes ulcerative colitis and Crohn's disease.

Sporadic tumour

A tumour that does not share tumorigenic mutations and/or other neoplastic changes in phenotype with the surrounding tissue.

Genetically mosaic

A feature of a group of cells that is composed of two or more clonal populations, each with a different genotype.

Driver mutations

Mutations that are positively selected for and are implicated in tumorigenesis.

Epistasis

The interaction of multiple genes that leads to the development of a phenotypic trait.

Polyclonal

An attribute of a lesion that is derived from two or more clones as opposed to a monoclonal origin.

Metachronous tumours

Primary tumours arising sequentially in time.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Curtius, K., Wright, N. & Graham, T. An evolutionary perspective on field cancerization. Nat Rev Cancer 18, 19–32 (2018). https://doi.org/10.1038/nrc.2017.102

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing