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  • Review Article
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Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis

Nature Reviews Cancer volume 10, pages 87–101 (2010)Cite this article

Subjects

Key Points

  • The paradigm that Barrett's oesophagus develops as a consequence of symptomatic gastroesophageal reflux disease and predisposes to oesophageal adenocarcinoma has dominated clinical thought for more than three decades. However, current approaches for controlling the incidence and mortality of oesophageal adenocarcinoma, which are largely based on endoscopic investigation of individuals with symptomatic gastroesophageal reflux disease, and histology-guided surveillance and treatment of individuals with Barrett's oesophagus, have considerable limitations.

  • Barrett's oesophagus rarely progresses to oesophageal adenocarcinoma, and a theory has recently been proposed that mucosal defences in most patients with Barrett's oesophagus represent successful adaptations to the harsh intra-oesophageal environment of chronic gastroesophageal reflux disease. Several mucosal defences that arise in Barrett's oesophagus have been identified, including the secretion of bicarbonate and mucous, expression of claudin 18 tight junctions, overexpression of defence and repair genes, and resistance to prolonged and repeated acid exposure.

  • The incidence of oesophageal adenocarcinoma has been rising at an alarming rate in the United States, Western Europe, Australia and in other developed countries over the past four decades, and there is disquieting evidence of increased incidence of oesophageal adenocarcinoma in some Asian populations.

  • Four risk factors — gastroesophageal reflux disease, obesity, cigarette smoking and poor diet — account for most oesophageal adenocarcinomas. The effects of obesity might influence both early and late stages of progression and interact biologically with gastroesophageal reflux disease, although a substantial proportion of the effect of obesity is likely to be through other pathways.

  • Neoplastic progression to oesophageal adenocarcinoma is characterized by genomic instability (including chromosomal instability in most cases), disruption of regulatory pathways and temporal evolution of clones that might be modulated by host and environmental risk and protective factors. Proper measurement and quantification of the complexity of these alterations creates opportunities and challenges for improved risk stratification, prevention and early detection.

  • Aspirin and other non-steroidal anti-inflammatory drugs have been consistently reported to have a protective association with oesophageal adenocarcinoma in case–control and cohort studies as well as meta-analyses; they might be useful in patients at both early and late stages of progression.

  • No intervention, whether based on lifestyle modification, chemoprevention or medical and surgical treatments, has yet been convincingly demonstrated in a randomized trial to reduce the incidence and/or mortality of oesophageal adenocarcinoma; this remains a particularly crucial area of unmet research need. New oesophageal adenocarcinoma prevention strategies are proposed to overcome these limitations.

Abstract

The public health importance of Barrett's oesophagus lies in its association with oesophageal adenocarcinoma. The incidence of oesophageal adenocarcinoma has risen at an alarming rate over the past four decades in many regions of the Western world, and there are indications that the incidence of this disease is on the rise in Asian populations in which it has been rare. Much has been learned of host and environmental risk factors that affect the incidence of oesophageal adenocarcinoma, and data indicate that patients with Barrett's oesophagus rarely develop oesophageal adenocarcinoma. Given that 95% of oesophageal adenocarcinomas arise in individuals without a prior diagnosis of Barrett's oesophagus, what strategies can be used to reduce late diagnosis of oesophageal adenocarcinoma?

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Figure 1: Barrett's specialized intestinal metaplasia and mucosal defence.
Figure 2: The paradox of Barrett's oesophagus.

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References

  1. Sharma, P. et al. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology 127, 310–330 (2004).

    Article  PubMed  Google Scholar 

  2. Vakil, N., van Zanten, S. V., Kahrilas, P., Dent, J. & Jones, R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am. J. Gastroenterol. 101, 1900–1920 (2006).

    Article  PubMed  Google Scholar 

  3. Barrett, N. Chronic peptic ulcer of the oesophagus and 'oesophagitis'. Br. J. Surg. 38, 175–182 (1950).

    Article  CAS  PubMed  Google Scholar 

  4. Allison, P. R. & Johnstone, A. S. The oesophagus lined with gastric mucous membrane. Thorax. 8, 87–101 (1953).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Naef, A. P., Savary, M. & Ozzello, L. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. Report on 140 cases of Barrett's esophagus with 12 adenocarcinomas. J. Thorac. Cardiovasc. Surg. 70, 826–835 (1975).

    CAS  PubMed  Google Scholar 

  6. Holmes, R. S. & Vaughan, T. L. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol. 17, 2–9 (2007).

    Article  PubMed  Google Scholar 

  7. Sampliner, R. E. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus. Am. J. Gastroenterol. 93, 1028–1032 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Hirota, W. K. et al. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc. 63, 570–580 (2006).

    Article  PubMed  Google Scholar 

  9. Orlando, R. C. Mucosal Defense in Barrett's Esophagus. Barrett's Esophagus and Esophageal Adenocarcinoma (S. R. ed. Sharma P) 60–72 (Blackwell Publishing, Ltd, Oxford, UK, 2006). This paper proposed the theory that Barrett's oesophagus is a successful adaptation to reflux, which is supported by studies described in References 38–42.

  10. Cairns, J. Mutation Selection and the Natural History of Cancer. Nature 255, 197–200 (1975).

    Article  CAS  PubMed  Google Scholar 

  11. Tobey, N. A., Argote, C. M., Vanegas, X. C., Barlow, W. & Orlando, R. C. Electrical parameters and ion species for active transport in human esophageal stratified squamous epithelium and Barrett's specialized columnar epithelium. Am. J. Physiol. Gastrointest. Liver Physiol. 293, 264–270 (2007).

    Article  CAS  Google Scholar 

  12. Dixon, J. et al. Esophageal mucin: an adherent mucus gel barrier is absent in the normal esophagus but present in columnar-lined Barrett's esophagus. Am. J. Gastroenterol. 96, 2575–2583 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Jovov, B. et al. Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G1106–G1113 (2007).

  14. Ostrowski, J. et al. Molecular defense mechanisms of Barrett's metaplasia estimated by an integrative genomics. J. Mol. Med. 85, 733–743 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Lao-Sirieix, P. et al. Physiological and molecular analysis of acid loading mechanisms in squamous and columnar-lined esophagus. Dis. Esophagus. 21, 529–538 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Sharma, P. et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus. Clin. Gastroenterol. Hepatol. 4, 566–572 (2006).

    Article  PubMed  Google Scholar 

  17. Schnell, T. G. et al. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology. 120, 1607–1619 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Conio, M. et al. Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study. Am. J. Gastroenterol. 98, 1931–1939 (2003).

    Article  PubMed  Google Scholar 

  19. Macdonald, C. E., Wicks, A. C. & Playford, R. J. Ten years' experience of screening patients with Barrett's oesophagus in a university teaching hospital. Gut 41, 303–307 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reid, B. J., Levine, D. S., Longton, G., Blount, P. L. & Rabinovitch, P. S. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am. J. Gastroenterol. 95, 1669–1676 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hage, M. et al. Oesophageal cancer incidence and mortality in patients with long-segment Barrett's oesophagus after a mean follow-up of 12.7 years. Scand. J. Gastroenterol. 39, 1175–1179 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Thomas, T., Abrams, K. R., De Caestecker, J. S. & Robinson, R. J. Meta analysis: cancer risk in Barrett's oesophagus. Aliment Pharmacol. Ther. 26, 1465–1477 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Yousef, F. et al. The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: a systematic review and meta-analysis. Am. J. Epidemiol. 168, 237–249 (2008). References 22 and 23 report the estimated annual rate of progression from Barrett's oesophagus to oesophageal adenocarcinoma, based on meta-analyses.

    Article  PubMed  Google Scholar 

  24. Anderson, L. A. et al. Mortality in Barrett's oesophagus: results from a population based study. Gut 52, 1081–1084 (2003). This study reports that death from oesophageal adenocarcinoma is rare in individuals with Barrett's oesophagus consistent with other reports including References 25 and 26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Conio, M. et al. Secular trends in the epidemiology and outcome of Barrett's oesophagus in Olmsted County, Minnesota. Gut 48, 304–309 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Moayyedi, P. et al. Mortality rates in patients with Barrett's oesophagus. Aliment Pharmacol. Ther. 27, 316–320 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Solaymani-Dodaran, M., Logan, R. F., West, J. & Card, T. Mortality associated with Barrett's esophagus and gastroesophageal reflux disease diagnoses-a population-based cohort study. Am. J. Gastroenterol. 100, 2616–2621 (2005).

    Article  PubMed  Google Scholar 

  28. Dulai, G. S., Guha, S., Kahn, K. L., Gornbein, J. & Weinstein, W. M. Preoperative prevalence of Barrett's esophagus in esophageal adenocarcinoma: a systematic review. Gastroenterology 122, 26–33 (2002).

    Article  PubMed  Google Scholar 

  29. Corley, D. A., Levin, T. R., Habel, L. A., Weiss, N. S. & Buffler, P. A. Surveillance and survival in Barrett's adenocarcinomas: a population-based study. Gastroenterology 122, 633–640 (2002).

    Article  PubMed  Google Scholar 

  30. Bytzer, P., Christensen, P. B., Damkier, P., Vinding, K. & Seersholm, N. Adenocarcinoma of the esophagus and Barrett's esophagus: a population- based study. Am. J. Gastroenterol. 94, 86–91 (1999). References 29 and 30 report that the vast majority of individuals who develop oesophageal adenocarcinoma do not have a prior diagnosis of Barrett's oesophagus, even if they have had a prior endoscopy.

    Article  CAS  PubMed  Google Scholar 

  31. Cooper, G. S., Kou, T. D. & Chak, A. Receipt of previous diagnoses and endoscopy and outcome from esophageal adenocarcinoma: a population-based study with temporal trends. Am. J. Gastroenterol. 104, 1356–1362 (2009).

    Article  PubMed  Google Scholar 

  32. Albertsen, P. C., Hanley, J. A. & Fine, J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293, 2095–2101 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Marcus, P. M. et al. Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J. Natl Cancer Inst. 98, 748–756 (2006).

    Article  PubMed  Google Scholar 

  34. Folkman, J. & Kalluri, R. Cancer without disease. Nature. 427, 787 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Chawla, S. N. et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J. Urol. 175, 425–431 (2006).

    Article  PubMed  Google Scholar 

  36. Brown, L. M., Devesa, S. S. & Chow, W. H. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J. Natl Cancer Inst. 100, 1184–1187 (2008). This paper presents the most recent data on oesophageal adenocarcinoma incidence trends in the United States.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bollschweiler, E., Wolfgarten, E., Gutschow, C. & Holscher, A. H. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer. 92, 549–555 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Fernandes, M. L., Seow, A., Chan, Y. H. & Ho, K. Y. Opposing trends in incidence of esophageal squamous cell carcinoma and adenocarcinoma in a multi-ethnic Asian country. Am. J. Gastroenterol. 101, 1430–1436 (2006).

    Article  PubMed  Google Scholar 

  39. Shibata, A., Matsuda, T., Ajiki, W. & Sobue, T. Trend in incidence of adenocarcinoma of the esophagus in Japan, 1993–2001 Jpn J. Clin. Oncol. 38, 464–468 (2008).

    Article  PubMed  Google Scholar 

  40. Haghdoost, A. A. et al. Rising incidence of adenocarcinoma of the esophagus in Kerman, Iran. Arch. Iran Med. 11, 364–370 (2008).

    PubMed  Google Scholar 

  41. Yee, Y. K., Cheung, T. K., Chan, A. O., Yuen, M. F. & Wong, B. C. Decreasing trend of esophageal adenocarcinoma in Hong Kong. Can. Epidemiol. Biomarkers Prev. 16, 2637–2640 (2007).

    Article  Google Scholar 

  42. Chung, J. W. et al. Unchanging trend of esophagogastric junction adenocarcinoma in Korea: experience at a single institution based on Siewert's classification. Dis. Esophagus 8, 676–681 (2009).

    Article  Google Scholar 

  43. Polednak, A. P. Trends in survival for both histologic types of esophageal cancer in US surveillance, epidemiology and end results areas. Int. J. Cancer 105, 98–100 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Farrow, D. C. et al. Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer. Cancer Causes Control 11, 231–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Lagergren, J., Bergstrom, R., Lindgren, A. & Nyren, O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. New England Journal of Medicine. 340, 825–831 (1999). References 44 and 45 report that nearly 50% of patients who develop oesophageal adenocarcinoma have no or an infrequent history of reflux symptoms.

    Article  CAS  PubMed  Google Scholar 

  46. Whiteman, D. C. et al. Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus. Gut 57, 173–180 (2008). This analysis describes the independent and joint effects of obesity, gastric reflux and smoking in a large population-based study in Australia.

    Article  CAS  PubMed  Google Scholar 

  47. Anderson, L. A. et al. Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study. World J. Gastroenterol. 13, 1585–1594 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wu, A. H., Tseng, C. C. & Bernstein, L. Hiatal hernia, reflux symptoms, body size, and risk of esophageal and gastric adenocarcinoma. Cancer 98, 940–948 (2003).

    Article  PubMed  Google Scholar 

  49. Vaughan, T. L., Davis, S., Kristal, A. & Thomas, D. B. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 4, 85–92 (1995).

    CAS  PubMed  Google Scholar 

  50. Chow, W. H. et al. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J. Natl Cancer Inst. 90, 150–155 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Samanic, C., Chow, W. H., Gridley, G., Jarvholm, B. & Fraumeni, J. F., Jr. Relation of body mass index to cancer risk in 362,552 Swedish men. Cancer Causes Control 17, 901–909 (2006).

    Article  PubMed  Google Scholar 

  52. Lindblad, M., Rodriguez, L. A. & Lagergren, J. Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and gastric non-cardia adenocarcinoma among men and women in a nested case-control study. Cancer Causes Control 16, 285–294 (2005).

    Article  PubMed  Google Scholar 

  53. Engeland, A., Tretli, S. & Bjorge, T. Height and body mass index in relation to esophageal cancer: 23-year follow-up of two million Norwegian men and women. Cancer Causes Control 15, 837–843 (2004).

    Article  PubMed  Google Scholar 

  54. MacInnis, R. J., English, D. R., Hopper, J. L. & Giles, G. G. Body size and composition and the risk of gastric and oesophageal adenocarcinoma. Int. J. Cancer 118, 2628–2631 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Steffen, A. et al. Anthropometry and Esophageal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol. Biomarkers Prev. 18, 2079–2089 (2009).

    Article  PubMed  Google Scholar 

  56. Corley, D. A., Kubo, A. & Zhao, W. Abdominal obesity and the risk of esophageal and gastric cardia carcinomas. Cancer Epidemiol. Biomarkers Prev. 17, 352–358 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Wu, A., Wan, P. & Bernstein, L. A multiethnic population-based study of smoking, alcohol and body size and risk of adenocarcinomas of the stomach and esophagus (United States). Cancer Causes Control 12, 721–732 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Kubo, A. & Corley, D. A. Body mass index and adenocarcinomas of the esophagus or gastric cardia: a systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 872–878 (2006).

    Article  PubMed  Google Scholar 

  59. Hampel, H., Abraham, N. S. & El-Serag, H. B. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann. Intern. Med. 143, 199–211 (2005).

    Article  PubMed  Google Scholar 

  60. Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004).

    Article  CAS  Google Scholar 

  61. Ogden, C. L. et al. Prevalence of overweight and obesity in the United States, 1999–2004 JAMA 295, 1549–1555 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Dollman, J. & Olds, T. S. Secular changes in fatness and fat distribution in Australian children matched for body size. Int. J. Pediatr. Obes. 1, 109–113 (2006).

    Article  PubMed  Google Scholar 

  63. Jeon, J., Luebeck, E. G. & Moolgavkar, S. H. Age effects and temporal trends in adenocarcinoma of the esophagus and gastric cardia (United States). Cancer Causes Control 17, 971–981 (2006).

    Article  PubMed  Google Scholar 

  64. Gammon, M. D. et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J. Natl Cancer Inst. 89, 1277–1284 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Mulholland, H. G. et al. Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Cancer Causes Control 20, 279–288 (2009).

    Article  PubMed  Google Scholar 

  66. Wu, A. H., Tseng, C. C., Hankin, J. & Bernstein, L. Fiber intake and risk of adenocarcinomas of the esophagus and stomach. Cancer Causes Control 18, 713–722 (2007).

    Article  PubMed  Google Scholar 

  67. Mayne, S. T. et al. Nutrient Intake and Risk of Subtypes of Esophageal and Gastric Cancer. Cancer Epidemiol. Biomarkers Prev. 10, 1055–1062 (2001).

    CAS  PubMed  Google Scholar 

  68. Anderson, L. A. et al. The association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Gastroenterology 136, 799–805 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Pandeya, N., Williams, G., Green, A. C., Webb, P. M. & Whiteman, D. C. Alcohol consumption and the risks of adenocarcinoma and squamous cell carcinoma of the esophagus. Gastroenterology 136, 1215–1224, e1–2 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. de Martel, C. et al. Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma. J. Infect. Dis. 191, 761–767 (2005).

    Article  PubMed  Google Scholar 

  71. Chow, W. H. et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res. 58, 588–590 (1998).

    CAS  PubMed  Google Scholar 

  72. Islami, F. & Kamangar, F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev. Res. (Phila Pa). 1, 329–338 (2008).

    Article  CAS  PubMed Central  Google Scholar 

  73. Blaser, M. J. Disappearing microbiota: helicobacter pylori protection against esophageal adenocarcinoma. Cancer Prev. Res. (Phila Pa). 1, 308–311 (2008).

    Article  Google Scholar 

  74. Engel, L. S. et al. Population attributable risks of esophageal and gastric cancers. J. Natl Cancer 95, 1404–1413 (2003). This is the first and only publication to date that describes the population-attributable risks of the major risk factors for oesophageal adenocarcinoma.

    Article  Google Scholar 

  75. Ronkainen, J. et al. Prevalence of Barrett's Esophagus in the General Population: an Endoscopic Study. Gastroenterol. 129, 1828–1831 (2005). This was the first paper to assess the population prevalence of Barrett's oesophagus.

    Article  Google Scholar 

  76. Zagari, R. M. et al. Gastro-oesophageal reflux symptoms, oesophagitis and Barrett's oesophagus in the general population: the Loiano-Monghidoro study. Gut 57, 1354–1359 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Kim, J. Y. et al. Prevalence of Barrett's esophagus in Korea. J. Gastroenterol. Hepatol. 20, 633–636 (2005).

    Article  PubMed  Google Scholar 

  78. Lim, S. L., Goh, W. T., Lee, J. M., Ng, T. P. & Ho, K. Y. Changing prevalence of gastroesophageal reflux with changing time: longitudinal study in an Asian population. J. Gastroenterol. Hepatol. 20, 995–1001 (2005).

    Article  PubMed  Google Scholar 

  79. Wu, J. C. Gastroesophageal reflux disease: an Asian perspective. J. Gastroenterol. Hepatol. 23, 1785–1793 (2008).

    Article  PubMed  Google Scholar 

  80. Vaughan TL. et al. NSAID use, BMI, and anthropometry in relation to genetic and cell cycle abnormalities in Barrett's Esophagus. Cancer Epidemiol. Biomarkers Prev. 11, 745–752 (2002).

    PubMed  Google Scholar 

  81. Edelstein, Z. R., Farrow, D. C., Bronner, M. P., Rosen, S. N. & Vaughan, T. L. Central adiposity and risk of Barrett's esophagus. Gastroenterology 133, 403–411 (2007).

    Article  PubMed  Google Scholar 

  82. Corley, D. A. et al. Abdominal obesity and body mass index as risk factors for Barrett's esophagus. Gastroenterology 133, 34–41 (2007). References 81 and 82 are the most recent that examine the role of abdominal obesity in the aetiology of Barrett's oesophagus.

    Article  PubMed  Google Scholar 

  83. El-Serag, H. B., Kvapil, P., Hacken-Bitar, J. & Kramer, J. R. Abdominal obesity and the risk of Barrett's esophagus. Am. J. Gastroenterol. 100, 2151–2156 (2005).

    Article  PubMed  Google Scholar 

  84. Barlow, W. J. & Orlando, R. C. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology 128, 771–778 (2005).

    Article  PubMed  Google Scholar 

  85. El-Serag, H. B., Tran, T., Richardson, P. & Ergun, G. Anthropometric correlates of intragastric pressure. Scand. J. Gastroenterol. 41, 887–891 (2006).

    Article  PubMed  Google Scholar 

  86. Corley, D. A. & Kubo, A. Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 101, 2619–2628 (2006).

    Article  PubMed  Google Scholar 

  87. Kendall, B. J. et al. Leptin and the risk of Barrett's oesophagus. Gut 57, 448–454 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Hursting, S. D. et al. Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. Best Pract Res. Clin. Endocrinol. Metab. 22, 659–669 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Edelstein, Z. R., Bronner, M. P., Rosen, S. N. & Vaughan, T. L. Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study. Am. J. Gastroenterol. 104, 834–842 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Smith, K. J., O'Brien, S. M., Green, A. C., Webb, P. M. & Whiteman, D. C. Increased Risks of Barrett's Esophagus With Smoking But not Self-Reported Body Mass Index. Clin. Gastroenterol. Hepatol. 8, 840–848 (2009).

    Article  Google Scholar 

  91. Kubo, A. et al. Cigarette smoking and the risk of Barrett's esophagus. Cancer Causes Control 20, 303–311 (2009).

    Article  PubMed  Google Scholar 

  92. Kubo, A. et al. Dietary antioxidants, fruits, and vegetables and the risk of Barrett's esophagus. Am. J. Gastroenterol. 103, 1614–1623 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Thompson, O. M., Beresford, S. A., Kirk, E. A. & Vaughan, T. L. Vegetable and fruit intakes and risk of Barrett's esophagus in men and women. Am. J. Clin. Nutr. 89, 890–896 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Risques, R. A. et al. Leukocyte telomere length predicts cancer risk in Barrett's esophagus. Cancer Epidemiol. Biomarkers Prev. 16, 2649–2655 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Valdes, A. M. et al. Obesity, cigarette smoking, and telomere length in women. Lancet 366, 662–664 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Demissie, S. et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell 5, 325–330 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Xing, J. et al. Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p is associated with an increased risk for esophageal cancer. Cancer Prev. Res. (Phila Pa). 2, 459–465 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  98. Poynton, A. R., Walsh, T. N., O'Sullivan, G. & Hennessy, T. P. Carcinoma arising in familial Barrett's esophagus. Am. J. Gastroenterol. 91, 1855–1856 (1996).

    CAS  PubMed  Google Scholar 

  99. Romero, Y. et al. Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 113, 1449–1456 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Groves, C., Jankowski, J., Barker, F. & Holdstock, G. A family history of Barrett's oesophagus: another risk factor? Scand. J. Gastroenterol. 40, 1127–1128 (2005).

    Article  PubMed  Google Scholar 

  101. Munitiz, V. et al. High risk of malignancy in familial Barrett's esophagus: presentation of one family. J. Clin. Gastroenterol. 42, 806–809 (2008).

    Article  PubMed  Google Scholar 

  102. Cameron, A. J. et al. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 122, 55–59 (2002).

    Article  PubMed  Google Scholar 

  103. Mohammed, I., Cherkas, L. F., Riley, S. A., Spector, T. D. & Trudgill, N. J. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut 52, 1085–1089 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chak, A. et al. Identification of Barrett's esophagus in relatives by endoscopic screening. Am. J. Gastroenterol. 99, 2107–2114 (2004).

    Article  PubMed  Google Scholar 

  105. Fitzgerald, R. C. Complex diseases in gastroenterology and hepatology: GERD, Barrett's, and esophageal adenocarcinoma. Clin. Gastroenterol. Hepatol. 3, 529–537 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Chak, A. et al. Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol. Biomarkers Prev. 15, 1668–1673 (2006).

    Article  PubMed  Google Scholar 

  107. Chak, A. et al. Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut 51, 323–328 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ochs-Balcom, H. M. et al. Consortium approach to identifying genes for Barrett's esophagus and esophageal adenocarcinoma. Transl. Res. 150, 3–17 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Drovdlic, C. M. et al. Demographic and phenotypic features of 70 families segregating Barrett's oesophagus and oesophageal adenocarcinoma. J. Med. Genet. 40, 651–656 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Casson, A. G. et al. Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Carcinogenesis 26, 1536–1541 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Terry, M. B. et al. Alcohol dehydrogenase 3 and risk of esophageal and gastric adenocarcinomas. Cancer Causes Control 18, 1039–1046 (2007).

    Article  PubMed  Google Scholar 

  112. Wideroff, L. et al. GST, NAT1, CYP1A1 polymorphisms and risk of esophageal and gastric adenocarcinomas. Cancer Detect Prev. 31, 233–236 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hiyama, T., Yoshihara, M., Tanaka, S. & Chayama, K. Genetic polymorphisms and esophageal cancer risk. Int. J. Cancer 121, 1643–1658 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Murphy, S. J. et al. A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis 28, 1323–1328 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Doecke, J. et al. Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma. Int. J. Cancer 123, 174–180 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. El-Omar, E. M. et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124, 1193–1201 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Ye, W. et al. The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma: a population-based case-control study in Sweden. Carcinogenesis 27, 1835–1841 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Di Martino, E. et al. IGFBP-3 and IGFBP-10 (CYR61) up-regulation during the development of Barrett's oesophagus and associated oesophageal adenocarcinoma: potential biomarkers of disease risk. Biomarkers 11, 547–561 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. di Martino, E. et al. The NAD(P)H:quinone oxidoreductase I C609T polymorphism modifies the risk of Barrett esophagus and esophageal adenocarcinoma. Genet. Med. 9, 341–347 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Elwood, P. C., Gallagher, A. M., Duthie, G. G., Mur, L. A. & Morgan, G. Aspirin, salicylates, and cancer. Lancet 373, 1301–1309 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Moons, L. M. et al. COX-2 CA-haplotype is a risk factor for the development of esophageal adenocarcinoma. Am. J. Gastroenterol. 102, 2373–2379 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Ferguson, H. R. et al. Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 17, 727–731 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Galipeau, P. C. et al. NSAIDs modulate CDKN2A, TP53, and DNA content risk for future esophageal adenocarcinoma. PLoS Med. 4, e67 (2007). This paper reported that chromosome instability markers identified individuals with Barrett's oesophagus at low and high risk of progression to oesophageal adenocarcinoma and that current users of aspirin or other NSAIDs had a strong and significant decreased risk of progression to cancer, especially in high-risk individuals with multiple chromosome instability markers.

  124. Anderson, L. A. et al. Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence. Cancer Res. 66, 4975–4982 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Corley, D. A., Kerlikowske, K., Verma, R. & Buffler, P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124, 47–56 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Farrow, D. C. et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol. Biomarkers Prev. 7, 97–102 (1998).

    CAS  PubMed  Google Scholar 

  127. Vaughan, T. L. et al. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study. Lancet Oncol. 6, 945–952 (2005). This is the first prospective study describing the inverse association between NSAID use and risk of progression to oesophageal adenocarcinoma among people with Barrett's oesophagus.

    Article  CAS  PubMed  Google Scholar 

  128. Chao, D. L. et al. Mutagen sensitivity and neoplastic progression in patients with Barrett's esophagus: a prospective analysis. Cancer Epidemiol. Biomarkers Prev. 15, 1935–1940 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Prentice, R. L. Surrogate endpoints in clinical trials: definition and operational criteria. Stat. Med. 8, 431–440 (1989).

    Article  CAS  PubMed  Google Scholar 

  130. Fleming, T. R., Prentice, R. L., Pepe, M. S. & Glidden, D. Surrogate and auxiliary endpoints in clinical trials, with potential applications in cancer and AIDS research. Stat Med 13, 955–968 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  132. Nancarrow, D. J. et al. Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays. Cancer Res. 68, 4163–4172 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Li, X. et al. Single nucleotide polymorphism-based genome-wide chromosome copy change, loss of heterozygosity, and aneuploidy in BE neoplastic progression. Can. Prev. Res. 1, 413–423 (2008).

    Article  CAS  Google Scholar 

  134. Jenkins, G. J. et al. Genetic pathways involved in the progression of Barrett's metaplasia to adenocarcinoma. Br. J. Surg. 89, 824–837 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. van Baal, J. W. et al. A comparative analysis by SAGE of gene expression profiles of Barrett's esophagus, normal squamous esophagus, and gastric cardia. Gastroenterology 129, 1274–1281 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. van Baal, J. W. et al. A comparative analysis by SAGE of gene expression profiles of esophageal adenocarcinoma and esophageal squamous cell carcinoma. Cell. Oncol. 30, 63–75 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Barrett, M. T. et al. Transcriptional analyses of Barrett's metaplasia and normal upper GI mucosae. Neoplasia 4, 121–128 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Helm, J. et al. Dedifferentiation precedes invasion in the progression from Barrett's metaplasia to esophageal adenocarcinoma. Clin. Cancer Res. 11, 2478–2485 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Peng, D. et al. Alterations in Barrett's-related adenocarcinomas: a proteomic approach. Int. J. Cancer. 122, 1303–1310 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Zhao, J. et al. Comparative proteomics analysis of Barrett metaplasia and esophageal adenocarcinoma using two-dimensional liquid mass mapping. Mol. Cell Proteomics. 6, 987–999 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Kraly, J. R. et al. Reproducible Two-Dimensional Capillary Electrophoresis Analysis of Barrett's Esophagus Tissues. Anal. Chem. 78, 5977–5986 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Rajagopalan, H., Nowak, M. A., Vogelstein, B. & Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nature Rev. Cancer 3, 695–701 (2003). This is an excellent overview of chromosomal instability and cancer.

    Article  CAS  Google Scholar 

  143. Wijnhoven, B. P., Tilanus, H. W. & Dinjens, W. N. Molecular biology of Barrett's adenocarcinoma. Ann. Surg. 233, 322–337 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Paulson, T. G. & Reid, B. J. Focus on Barrett's esophagus and esophageal adenocarcinoma. Cancer Cell 6, 11–16 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Lai, L. A. et al. Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH. Genes Chromosomes Cancer 46, 532–542 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. 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).

    Article  CAS  PubMed  Google Scholar 

  147. Leedham, S. J. et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus. Gut 57, 1041–1048 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Barrett, M. T. et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nature Gen. 22, 106–109 (1999).

    Article  CAS  Google Scholar 

  149. Fritcher, E. G. et al. A comparison of conventional cytology, DNA ploidy analysis, and fluorescence in situ hybridization for the detection of dysplasia and adenocarcinoma in patients with Barrett's esophagus. Hum. Pathol. 39, 1128–1135 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Paulson, T. G. et al. Chromosomal instability and copy number alterations in Barrett's esophagus and esophageal adenocarcinoma. Clin. Cancer Res. 15, 3305–3314 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kissel, H. D., Galipeau, P. C., Li, X. & Reid, B. J. Translation of an STR-based biomarker into a clinically compatible SNP-based platform for loss of heterozygosity. Cancer Biomark. 5, 143–158 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Smith, E. et al. Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma. Mol. Cancer. 7, 75 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Jin, Z. et al. A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus. Cancer Res. 69, 4112–4115 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Wang, J. S. et al. DNA Promoter Hypermethylation of p16 and APC Predicts Neoplastic Progression in Barrett's Esophagus. Am. J. Gastroenterol. (2009).

  155. Rakyan, V. K. et al. An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome Res. 18, 1518–1529 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bloushtain-Qimron, N., Yao, J., Shipitsin, M., Maruyama, R. & Polyak, K. Epigenetic patterns of embryonic and adult stem cells. Cell Cycle 8, 809–817 (2009).

    Article  CAS  PubMed  Google Scholar 

  157. Irizarry, R. A. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genet. 41, 178–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Breivik, J. The evolutionary origin of genetic instability in cancer development. Semin. Cancer Biol. 15, 51–60 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  160. Maley, C. C. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nature Genet. 38, 468–473 (2006). This was the first report to show that genetic clonal diversity was a predictor of progression from Barrett's oesophagus to oesophageal adenocarcinoma.

    Article  CAS  PubMed  Google Scholar 

  161. Ouatu-Lascar, R., Fitzgerald, R. C. & Triadafilopoulos, G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression. Gastroenterology 117, 327–335 (1999).

    Article  CAS  PubMed  Google Scholar 

  162. Sirieix, P. S. et al. Surface expression of minichromosome maintenance proteins provides a novel method for detecting patients at risk for developing adenocarcinoma in Barrett's esophagus. Clin. Cancer Res. 9, 2560–2566 (2003).

    CAS  PubMed  Google Scholar 

  163. Murray, L. et al. TP53 and progression from Barrett's metaplasia to oesophageal adenocarcinoma in a UK population cohort. Gut 55, 1390–1397 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bani-Hani, K. et al. Prospective study of cyclin D1 overexpression in Barrett's esophagus: association with increased risk of adenocarcinoma. J. Natl Cancer Inst. 92, 1316–1321 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Brosh, R. & Rotter, V. When mutants gain new powers: news from the mutant p53 field. Nature Rev. Cancer 9, 701–713 (2009).

    Article  CAS  Google Scholar 

  166. Chao, D. L. et al. Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett's esophagus: a long-term prospective study. Clin. Cancer Res. 14, 6988–6995 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Shaheen, N. & Ransohoff, D. F. Gastroesophageal reflux, barrett esophagus, and esophageal cancer: scientific review. JAMA 287, 1972–1981 (2002).

    Article  PubMed  Google Scholar 

  168. Wang, K. K. & Sampliner, R. E. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am. J. Gastroenterol. 103, 788–797 (2008).

    Article  PubMed  Google Scholar 

  169. Kahrilas, P. J., Shaheen, N. J. & Vaezi, M. F. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 135, 1392–1413, 1413 e1–5 (2008).

    Article  PubMed  Google Scholar 

  170. Kelloff, G. J. et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward. Clin. Cancer Res. 12, 3661–3697 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Local Government Actions to Prevent Childhood Obesity. Institute of Medicine and National Research Council. Sep 1 2009. http://www.iom.edu/en/Reports/2009/ChildhoodObesityPreventionLocalGovernments.aspx.

  172. Lao-Sirieix, P. et al. Non-endoscopic screening biomarkers for Barrett's oesophagus: from microarray analysis to the clinic. Gut 58, 1451–1459 (2009). This study describes progress in developing non-endoscopic screening for Barrett's oesophagus.

    Article  CAS  PubMed  Google Scholar 

  173. Streitz, J., J. M., Andrews, J., C. W. & Ellis, F. H. Endoscopic Surveillance of Barrett's Esophagus. J. Thorac. Cardiovasc.Surg. 105, 383–388 (1993).

    PubMed  Google Scholar 

  174. Peters, J. H. et al. Outcome of adenocarcinoma arising in Barrett's esophagus in endoscopically surveyed and nonsurveyed patients. J. Thorac Cardiovasc. Surg. 108, 813–821; discussion 821–822 (1994).

    CAS  PubMed  Google Scholar 

  175. van Sandick, J. W. et al. Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma. Gut 43, 216–222 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Incarbone, R., Bonavina, L., Saino, G., Bona, D. & Peracchia, A. Outcome of esophageal adenocarcinoma detected during endoscopic biopsy surveillance for Barrett's esophagus. Surg. Endosc. 16, 263–266 (2002).

    Article  CAS  PubMed  Google Scholar 

  177. Ferguson, M. K. & Durkin, A. Long-term survival after esophagectomy for Barrett's adenocarcinoma in endoscopically surveyed and nonsurveyed patients. J. Gastrointest Surg. 6, 29–35; discussion 36 (2002).

    Article  PubMed  Google Scholar 

  178. Fountoulakis, A. et al. Effect of surveillance of Barrett's oesophagus on the clinical outcome of oesophageal cancer. Br. J. Surg. 91, 997–1003 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Rubenstein, J. H., Sonnenberg, A., Davis, J., McMahon, L. & Inadomi, J. M. Effect of a prior endoscopy on outcomes of esophageal adenocarcinoma among United States veterans. Gastrointest Endosc. 68, 849–855 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Abnet, C. C. et al. Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis. Br. J. Cancer 100, 551–557 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Buttar, N. S. et al. Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett's esophagus. Gastroenterology 122, 1101–1112 (2002).

    Article  CAS  PubMed  Google Scholar 

  182. Duan, L., Wu, A. H., Sullivan-Halley, J. & Bernstein, L. Nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric adenocarcinomas in Los Angeles County. Cancer Epidemiol. Biomarkers Prev. 17, 126–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Sadeghi, S. et al. Aspirin, nonsteroidal anti-inflammatory drugs, and the risks of cancers of the esophagus. Cancer Epidemiol. Biomarkers Prev. 17, 1169–1178 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Heath, E. I. et al. Secondary chemoprevention of Barrett's esophagus with celecoxib: results of a randomized trial. J. Natl Cancer Inst. 99, 545–557 (2007).

    Article  CAS  PubMed  Google Scholar 

  185. Shar, A. O. et al. Modeling using baseline characteristics in a small multicenter clinical trial for Barrett's esophagus. Contemp. Clin. Trials 30, 2–7 (2009).

    Article  PubMed  Google Scholar 

  186. Nguyen, D. M. et al. Medication Usage and the Risk of Neoplasia in Patients With Barrett's Esophagus. Clin. Gastroenterol. Hepatol. (2009).

  187. Cooper, B. T., Chapman, W., Neumann, C. S. & Gearty, J. C. Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence. Aliment Pharmacol. Ther. 23, 727–733 (2006).

    Article  CAS  PubMed  Google Scholar 

  188. Feagins, L. A. et al. Acid has antiproliferative effects in nonneoplastic Barrett's epithelial cells. Am. J. Gastroenterol. 102, 10–20 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Das, D. et al. Management of Barrett's esophagus in the UK: overtreated and underbiopsied but improved by the introduction of a national randomized trial. Am. J. Gastroenterol. 103, 1079–1089 (2008).

    Article  PubMed  Google Scholar 

  190. Overholt, B. F. et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc. 62, 488–498 (2005).

    Article  PubMed  Google Scholar 

  191. Overholt, B. F. et al. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia. Gastrointest Endosc. 66, 460–468 (2007).

    Article  PubMed  Google Scholar 

  192. Shaheen, N. J. et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N. Engl. J. Med. 360, 2277–2288 (2009).

    Article  CAS  PubMed  Google Scholar 

  193. Pouw, R. E. et al. Eradication of Barrett esophagus with early neoplasia by radiofrequency ablation, with or without endoscopic resection. J. Gastrointest Surg. 12, 1627–1636; discussion 1636–1637 (2008).

    Article  PubMed  Google Scholar 

  194. Mork, H., Al-Taie, O., Berlin, F., Kraus, M. R. & Scheurlen, M. High recurrence rate of Barrett's epithelium during long-term follow-up after argon plasma coagulation. Scand. J. Gastroenterol. 42, 23–27 (2007).

    Article  PubMed  Google Scholar 

  195. Jenkins, G. J. et al. The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS. Mutagenesis 23, 399–405 (2008).

    Article  CAS  PubMed  Google Scholar 

  196. Grisham, M. B., Jourd'heuil, D. & Wink, D. A. Review article: chronic inflammation and reactive oxygen and nitrogen metabolism--implications in DNA damage and mutagenesis. Aliment Pharmacol. Ther. 14 Suppl 1, 3–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  197. Sihvo, E. I. et al. Oxidative stress has a role in malignant transformation in Barrett's oesophagus. Int. J. Cancer 102, 551–555 (2002).

    Article  CAS  PubMed  Google Scholar 

  198. Trayhurn, P., Bing, C. & Wood, I. S. Adipose tissue and adipokines--energy regulation from the human perspective. J. Nutr. 136, 1935S–1939S (2006).

    Article  CAS  PubMed  Google Scholar 

  199. von Zglinicki, T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339–344 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Turker, M. S. et al. A novel signature mutation for oxidative damage resembles a mutational pattern found commonly in human cancers. Cancer Res. 59, 1837–1839 (1999).

    CAS  PubMed  Google Scholar 

  201. Reid, B. J. et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum. Pathol. 19, 166–178 (1988).

    Article  CAS  PubMed  Google Scholar 

  202. Montgomery, E. et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum. Pathol. 32, 368–378 (2001).

    Article  CAS  PubMed  Google Scholar 

  203. Cameron, A. J. & Carpenter, H. A. Barrett's esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study. Am. J. Gastroenterol. 92, 586–591 (1997).

    CAS  PubMed  Google Scholar 

  204. Ofman, J. J. et al. The economic impact of the diagnosis of dysplasia in Barrett's esophagus. Am. J. Gastroenterol. 95, 2946–2952 (2000).

    Article  CAS  PubMed  Google Scholar 

  205. Weston, A. P. et al. p53 protein overexpression in low grade dysplasia (LGD) in Barrett's esophagus: immunohistochemical marker predictive of progression. Am. J. Gastroenterol. 96, 1355–1362 (2001).

    Article  CAS  PubMed  Google Scholar 

  206. Gatenby, P. et al. Routinely diagnosed low-grade dysplasia in Barrett's oesophagus: a population-based study of natural history. Histopathology 54, 814–819 (2009).

    Article  PubMed  Google Scholar 

  207. Dulai, G. S. et al. Dysplasia and risk of further neoplastic progression in a regional Veterans Administration Barrett's cohort. Am. J. Gastroenterol. 100, 775–783 (2005).

    Article  PubMed  Google Scholar 

  208. Buttar, N. S. et al. Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma. Gastroenterology. 120, 1630–1639 (2001).

    Article  CAS  PubMed  Google Scholar 

  209. Srivastava, A. et al. Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett's esophagus. Am. J. Gastroenterol. 102, 483–493; quiz 694 (2007).

    Article  PubMed  Google Scholar 

  210. Kaye, P. V. et al. Barrett's dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry. Histopathology 54, 699–712 (2009).

    Article  PubMed  Google Scholar 

  211. Fitzgerald, R. C. Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma. Gut 55, 1810–1820 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Haibe-Kains, B. et al. Comparison of prognostic gene expression signatures for breast cancer. BMC Genomics 9, 394 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Dumur, C. I. et al. Interlaboratory performance of a microarray-based gene expression test to determine tissue of origin in poorly differentiated and undifferentiated cancers. J. Mol. Diagn. 10, 67–77 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Levine, D. S., Reid, B. J., Haggitt, R. C., Rubin, C. E. & Rabinovitch, P. S. Correlation of ultrastructural aberrations with dysplasia and flow cytometric abnormalities in Barrett's epithelium. Gastroenterology 96, 355–367 (1989).

    Article  CAS  PubMed  Google Scholar 

  215. Khoury, M. J. et al. A Decade of Public Health Genomics in the United States: centers for Disease Control and Prevention 1997–2007. Public Health Genomics 1, 20–29 (2008).

    Google Scholar 

  216. Ampt, A. J. et al. Attitudes, norms and controls influencing lifestyle risk factor management in general practice. BMC Fam Pract. 10, 59 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Cook, M. B. et al. Risk of mortality and cancer incidence in Barrett's esophagus. Cancer Epidemiol. Biomarkers Prev. 16, 2090–2096 (2007).

    Article  PubMed  Google Scholar 

  218. Jankowski, J. & Barr, H. Improving surveillance for Barrett's oesophagus: AspECT and BOSS trials provide an evidence base. BMJ 332, 1512 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was funded by National Institutes of Health grants NIH P01CA091955 and NIH K05CA124911. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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Authors and Affiliations

  1. Divisions of Public Health Sciences and Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, 98109, USA

    Brian J. Reid, Xiaohong Li, Patricia C. Galipeau & Thomas L. Vaughan

  2. Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, 98109, USA

    Brian J. Reid & Patricia C. Galipeau

  3. Departments of Medicine, University of Washington, Seattle, 98109, USA

    Brian J. Reid

  4. Genome Sciences, University of Washington, Seattle, 98109, USA

    Brian J. Reid

  5. Epidemiology, University of Washington, Seattle, 98109, USA

    Thomas L. Vaughan

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DATABASES

OMIM

APC

CDKN2A

COX2

FHIT

MGMT

MYC

NQO1

TP53

Glossary

Oesophageal specialized intestinal metaplasia

Specialized intestinal metaplasia is a differentiated epithelium with crypt architecture that resembles the epithelium of the intestine, rather than that of the oesophagus.

Person-years

The denominator used in calculation of an incidence rate. It takes into account both the number of people being observed and the period of observation. For example, 1,000 people observed for 4 years would yield 4,000 person-years.

Overdiagnosis

Diagnosis of a disease or condition by screening that would not have been detected during the lifespan of the individual without screening.

Period effects

In statistical modelling of temporal trends of a disease, period effects are attributed to causes linked to calendar year, rather than age or year of birth.

p-trend

A statistical test to determine whether an association between an exposure and a disease is consistent with a monotonic relationship.

Manometry

A test to measure electrical and motor activity in the stomach.

Longitudinal studies

Observational studies in which the disease (and perhaps exposure) experience of a group of individuals is observed over multiple time points.

Chromosomal instability

An increased rate of gain or loss of whole chromosomes or large proportions of chromosomes.

Interstitial deletion

A deletion of variable size that does not involve the terminal parts of a chromosome.

CpG island

The CG island is a short stretch of DNA in which the frequency of the CG sequence is higher than in other regions. The p indicates that C and G are connected by a phosphodiester bond.

Shannon Index

Combines both the number and relative abundance of clones. It is also known as the information content or entropy.

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Reid, B., Li, X., Galipeau, P. et al. Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer 10, 87–101 (2010). https://doi.org/10.1038/nrc2773

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