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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Transcriptomes of the tumor-adjacent normal tissues are more informative than tumors in predicting recurrence in colorectal cancer patients
Journal of Translational Medicine Open Access 21 March 2023
Genetic, DNA methylation, and immune profile discrepancies between early-stage single primary lung cancer and synchronous multiple primary lung cancer
Clinical Epigenetics Open Access 07 January 2023
Global microRNA expression profile in laryngeal carcinoma unveils new prognostic biomarkers and novel insights into field cancerization
Scientific Reports Open Access 12 October 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
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.
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).
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).
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).
Bostwick, D. G. & Cheng, L. Precursors of prostate cancer. Histopathology 60, 4–27 (2012).
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).
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).
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).
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).
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.
Blanpain, C. & Simons, B. D. Unravelling stem cell dynamics by lineage tracing. Nat. Rev. Mol. Cell Biol. 14, 489–502 (2013).
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).
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).
Kim, K. M., Calabrese, P., Tavare, S. & Shibata, D. Enhanced stem cell survival in familial adenomatous polyposis. Am. J. Pathol. 164, 1369–1377 (2004).
Vortmeyer, A. O. & Alomari, A. K. Pathology of the nervous system in Von Hippel-Lindau disease. J. Kidney Cancer VHL 2, 114–129 (2015).
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.
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.
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.
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).
Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).
Lochhead, P. et al. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod. Pathol. 28, 14–29 (2015).
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.
Calabrese, P., Tavare, S. & Shibata, D. Pretumor progression: clonal evolution of human stem cell populations. Am. J. Pathol. 164, 1337–1346 (2004).
Greaves, M. Evolutionary determinants of cancer. Cancer Discov. 5, 806–820 (2015).
Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).
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.
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).
Jonason, A. S. et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 93, 14025–14029 (1996).
Sanchez-Danes, A. et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536, 298–303 (2016).
Bonilla, X. et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat. Genet. 48, 398–406 (2016).
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.
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.
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.
Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).
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).
Bieging, K. T., Mello, S. S. & Attardi, L. D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 14, 359–370 (2014).
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.
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).
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.
Curvers, W. L. et al. Low-grade dysplasia in Barrett's esophagus: overdiagnosed and underestimated. Am. J. Gastroenterol. 105, 1523–1530 (2010).
Kerkhof, M. et al. Grading of dysplasia in Barrett's oesophagus: substantial interobserver variation between general and gastrointestinal pathologists. Histopathology 50, 920–927 (2007).
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.
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.
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).
de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).
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).
Burd, E. M. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 16, 1–17 (2003).
Yakirevich, E. & Resnick, M. B. Pathology of gastric cancer and its precursor lesions. Gastroenterol. Clin. North Am. 42, 261–284 (2013).
Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).
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).
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).
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.
Robles, A. I. et al. Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology 150, 931–943 (2016).
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).
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).
Curtius, K. et al. A molecular clock infers heterogeneous tissue age among patients with Barrett's esophagus. PLoS Comput. Biol. 12, e1004919 (2016).
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
Thirlwell, C. et al. Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. Gastroenterology 138, 1441–1454 (2010).
Lin, J. et al. Polyclonality of BRAF mutations in acquired melanocytic nevi. J. Natl Cancer Inst. 101, 1423–1427 (2009).
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).
Bjerknes, M. & Cheng, H. Colossal crypts bordering colon adenomas in ApcMin mice express full-length Apc. Am. J. Pathol. 154, 1831–1834 (1999).
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).
Fernandez-Sanchez, M. E. et al. Mechanical induction of the tumorigenic beta-catenin pathway by tumour growth pressure. Nature 523, 92–95 (2015).
Martens, E. A., Kostadinov, R., Maley, C. C. & Hallatschek, O. Spatial structure increases the waiting time for cancer. New J. Phys. 13, 115014 (2011).
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).
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.
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).
Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).
Doupe, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093 (2012).
Teixeira, V. H. et al. Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors. eLife 2, e00966 (2013).
Nystul, T. & Spradling, A. An epithelial niche in the Drosophila ovary undergoes long-range stem cell replacement. Cell Stem Cell 1, 277–285 (2007).
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).
Frieda, K. L. et al. Synthetic recording and in situ readout of lineage information in single cells. Nature 541, 107–111 (2017).
McKenna, A. et al. Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353, aaf7907 (2016).
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).
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).
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).
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).
Korolev, K. S., Xavier, J. B. & Gore, J. Turning ecology and evolution against cancer. Nat. Rev. Cancer 14, 371–380 (2014).
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).
Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
Davis, H. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 21, 62–70 (2015).
Rutter, M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451–459 (2004).
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.
Bronisz, A. et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat. Cell Biol. 14, 159–167 (2011).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
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).
Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).
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.
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).
Welch, H. G. & Black, W. C. Overdiagnosis in cancer. J. Natl Cancer Inst. 102, 605–613 (2010).
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).
Greaves, M. F., Maia, A. T., Wiemels, J. L. & Ford, A. M. Leukemia in twins: lessons in natural history. Blood 102, 2321–2333 (2003).
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.
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).
Spechler, S. J. Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA 310, 627–636 (2013).
Greaves, M. Does everyone develop covert cancer? Nat. Rev. Cancer 14, 209–210 (2014). This commentary elegantly discusses the inevitably of cancerization.
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).
Odze, R. D. Diagnosis and grading of dysplasia in Barrett's oesophagus. J. Clin. Pathol. 59, 1029–1038 (2006).
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).
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).
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).
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).
Silvestri, G. A. et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N. Engl. J. Med. 373, 243–251 (2015).
Spira, A. et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat. Med. 13, 361–366 (2007).
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).
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
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.
Martinez, P. et al. Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus. Nat. Commun. 7, 12158 (2016).
Andor, N. et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat. Med. 22, 105–113 (2016).
Maley, C. C. et al. The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res. 64, 7629–7633 (2004).
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).
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.
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.
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).
Hanin, L. & Pavlova, L. Optimal screening schedules for prevention of metastatic cancer. Stat. Med. 32, 206–219 (2013).
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).
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).
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).
Galipeau, P. C. et al. NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med. 4, e67 (2007).
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.
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).
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).
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).
Gee, J., Sabichi, A. L. & Grossman, H. B. Chemoprevention of superficial bladder cancer. Crit. Rev. Oncol. Hematol. 43, 277–286 (2002).
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).
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).
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).
Foo, J., Leder, K. & Ryser, M. D. Multifocality and recurrence risk: a quantitative model of field cancerization. J. Theor. Biol. 355, 170–184 (2014).
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).
Rutgeerts, P. et al. Predictability of the postoperative course of Crohn's disease. Gastroenterology 99, 956–963 (1990).
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).
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).
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).
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.
Campbell, J. D. et al. The case for a Pre-Cancer Genome Atlas (PCGA). Cancer Prev. Res. 9, 119–124 (2016).
Koizumi, K. et al. Array-based identification of common DNA methylation alterations in ulcerative colitis. Int. J. Oncol. 40, 983–994 (2012).
van Dekken, H. et al. Genomic analysis of a case of multifocal adenocarcinoma in ulcerative colitis. Virchows Arch. 449, 716–721 (2006).
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).
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).
Damania, D. et al. Nanocytology of rectal colonocytes to assess risk of colon cancer based on field cancerization. Cancer Res. 72, 2720–2727 (2012).
Hawthorn, L., Lan, L. & Mojica, W. Evidence for field effect cancerization in colorectal cancer. Genomics 103, 211–221 (2014).
Kamiyama, H. et al. DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene 31, 5029–5037 (2012).
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).
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).
Shen, L. et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J. Natl Cancer Inst. 97, 1330–1338 (2005).
Gutierrez-Gonzalez, L. et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 140, 1251–1260.e6 (2011).
Kang, G. H. et al. Genetic evidence for the multicentric origin of synchronous multiple gastric carcinoma. Lab. Invest. 76, 407–417 (1997).
Takeshima, H. et al. Frequent involvement of chromatin remodeler alterations in gastric field cancerization. Cancer Lett. 357, 328–338 (2015).
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).
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).
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).
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).
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).
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).
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).
Roesch-Ely, M. et al. Proteomic analysis of field cancerization in pharynx and oesophagus: a prospective pilot study. J. Pathol. 221, 462–470 (2010).
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).
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).
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).
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).
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).
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).
McCaughan, F. et al. Genomic evidence of pre-invasive clonal expansion, dispersal and progression in bronchial dysplasia. J. Pathol. 224, 153–159 (2011).
Pipinikas, C. P. et al. Cell migration leads to spatially distinct but clonally related airway cancer precursors. Thorax 69, 548–557 (2014).
Sozzi, G. et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 55, 135–140 (1995).
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).
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).
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).
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).
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).
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).
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).
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).
Califano, J. et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 56, 2488–2492 (1996).
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).
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).
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).
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).
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).
Ellsworth, D. L. et al. Outer breast quadrants demonstrate increased levels of genomic instability. Ann. Surg. Oncol. 11, 861–868 (2004).
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).
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).
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).
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).
Nonn, L., Ananthanarayanan, V. & Gann, P. H. Evidence for field cancerization of the prostate. Prostate 69, 1470–1479 (2009).
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).
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).
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).
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).
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).
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).
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).
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).
Shain, A. H. et al. The genetic evolution of melanoma from precursor lesions. N. Engl. J. Med. 373, 1926–1936 (2015).
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.).
The authors declare no competing financial interests.
- Cell lineage
A group of cells that share a recent common ancestor cell; also known as a clone.
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.
A feature of tissues in which cells have an abnormal morphology or arrangement, usually regarded as being an unequivocal neoplastic alteration.
A feature of tissues in which an increase in cell number occurs without malignant change.
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.
The interaction of multiple genes that leads to the development of a phenotypic trait.
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
About this article
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
This article is cited by
Genetic, DNA methylation, and immune profile discrepancies between early-stage single primary lung cancer and synchronous multiple primary lung cancer
Clinical Epigenetics (2023)
Transcriptomes of the tumor-adjacent normal tissues are more informative than tumors in predicting recurrence in colorectal cancer patients
Journal of Translational Medicine (2023)
Expressional variations of Kaiso: an association with pathological characteristics and field cancerization of OSCC
BMC Cancer (2022)
Comparison of tumor and two types of paratumoral tissues highlighted epigenetic regulation of transcription during field cancerization in non-small cell lung cancer
BMC Medical Genomics (2022)
NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment