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Molecular Pathology of Barrett’s Metaplasia and Esophageal Adenocarcinoma

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Molecular Pathology of Neoplastic Gastrointestinal Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 7))

Abstract

Barrett’s metaplasia (BM), also called Barrett’s esophagus, is a condition in which the normal squamous lining of the esophagus is replaced to variable extent by columnar epithelium containing intestinal-type goblet cells. It is generally believed to be a complication of chronic gastroesophageal reflux disease (GERD), with obesity, smoking, and alcohol considered contributing factors. Persons with BM have a significantly increased risk for the development of esophageal adenocarcinoma that has been on the rise in the USA and Western Europe since the 1970s and is associated with poor survival. Early detection and surgical resection, when the tumor is still at an early stage, offer the best chance for survival. Understanding the molecular basis of this disease is essential to developing effective prevention and treatment strategies. In this chapter, we review the molecular changes that occur during the progression from normal squamous epithelium to BM and eventually to adenocarcinoma. We also discuss clinical relevance of some of the most common molecular markers.

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References

  1. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis. Surveillance and therapy of Barrett’s Esophagus. Am J Gastroenterol. 2008;103(3):788–797.

    Article  PubMed  Google Scholar 

  2. Younes M, Miller CC. Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol. 2002;37(12):1359–1365.

    Article  PubMed  CAS  Google Scholar 

  3. Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst. 2008;100(16):1184–1187.

    Article  PubMed  Google Scholar 

  4. Cen P, Banki F, Cheng L, Khalil K, Du XL, Fallon M, et al. Changes in age, stage distribution, and survival of patients with esophageal adenocarcinoma over three decades in the United States. Ann Surg Oncol. 2012;19:1685–1691.

    Article  PubMed  Google Scholar 

  5. Hong J, Resnick M, Behar J, Wang LJ, Wands J, DeLellis RA, et al. Acid-induced p16 hypermethylation contributes to development of esophageal adenocarcinoma via activation of NADPH oxidase NOX5-S. Am J Physiol Gastrointest Liver Physiol. 2010;299(3):G697–706.

    Article  PubMed  CAS  Google Scholar 

  6. Xiao H, Li T-KK, Yang J-MM, Liu LF. Acidic pH induces topoisomerase II-mediated DNA damage. Proc Natl Acad Sci USA. 2003;100(9):5205–5210.

    Article  PubMed  CAS  Google Scholar 

  7. Hamoui N, Peters JH, Schneider S, Uchida K, Yang D, Vallb ohmer D, et al. Increased acid exposure in patients with gastroesophageal reflux disease influences cyclooxygenase-2 gene expression in the squamous epithelium of the lower esophagus. Arch Surg. 2004;139(7):712-6. discussion 716–7.

    Article  PubMed  CAS  Google Scholar 

  8. Carlson N, Lechago J, Richter J, Sampliner RE, Peterson L, Santella RM, et al. Acid suppression therapy may not alter malignant progression in Barrett’s metaplasia showing p53 protein accumulation. Am J Gastroenterol. 2002;97(6):1340–1345.

    Article  PubMed  CAS  Google Scholar 

  9. Lao-Sirieix P, Roy A, Worrall C, Vowler SL, Gardiner S, Fitzgerald RC. Effect of acid suppression on molecular predictors for esophageal cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(2):288–293.

    Article  PubMed  CAS  Google Scholar 

  10. Abu-Sneineh A, Tam W, Schoeman M, Fraser R, Ruszkiewicz AR, Smith E, et al. The effects of high-dose esomeprazole on gastric and oesophageal acid exposure and molecular markers in Barrett’s oesophagus. Aliment Pharmacol Ther. 2010;32(8):1023–1030.

    Article  PubMed  CAS  Google Scholar 

  11. Jenkins GJS, D’Souza FR, Suzen SH, Eltahir ZS, James SA, Parry JM, et al. Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: The potential role of anti-oxidants in Barrett’s oesophagus. Carcinogenesis. 2007; 28(1):136–142.

    Article  PubMed  CAS  Google Scholar 

  12. Liu L, Ergun G, Ertan A, Woods K, Sachs I, Younes M. Detection of oxidative DNA damage in oesophageal biopsies of patients with reflux symptoms and normal pH monitoring. Aliment Pharmacol Ther. 2003;18(7):693–698.

    Article  PubMed  CAS  Google Scholar 

  13. Jenkins GJS, Harries K, Doak SH, Wilmes A, Griffiths AP, Baxter JN, et al. The bile acid deoxycholic acid (DCA) at neutral pH activates NF-kappaB and induces IL-8 expression in oesophageal cells in vitro. Carcinogenesis. 2004;25(3):317–323.

    Article  PubMed  CAS  Google Scholar 

  14. Huo X, Juergens S, Zhang X, Rezaei D, Yu C, Strauch ED, et al. Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-\kappa\B activation in benign Barrett’s epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;301: 278–86.

    Article  CAS  Google Scholar 

  15. Freund JN, Domon-Dell C, Kedinger M, Duluc I. The Cdx-1 and Cdx-2 homeobox genes in the intestine. Biochem Cell Biol. 1998;76(6):957–969.

    PubMed  CAS  Google Scholar 

  16. Eda A, Osawa H, Satoh K, Yanaka I, Kihira K, Ishino Y, et al. Aberrant expression of CDX2 in Barrett’s epithelium and inflammatory esophageal mucosa. J Gastroenterol. 2003;38(1): 14–22.

    Article  PubMed  CAS  Google Scholar 

  17. Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, et al. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. Gut. 2004;53(10):1416–1423.

    Article  PubMed  CAS  Google Scholar 

  18. Mutoh H, Hakamata Y, Sato K, Eda A, Yanaka I, Honda S, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun. 2002;294(2):470–479.

    Article  PubMed  CAS  Google Scholar 

  19. Silberg DG, Sullivan J, Kang E, Swain GP, Moffett J, Sund NJ, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology. 2002;122(3):689-696.

    Article  PubMed  CAS  Google Scholar 

  20. Marchetti M, Caliot E, Pringault E. Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes. J Cell Sci. 2003;116(Pt 8):1429–1436.

    Article  PubMed  CAS  Google Scholar 

  21. Kazumori H, Ishihara S, Rumi MAK, Kadowaki Y, Kinoshita Y. Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett’s epithelium. Gut. 2006;55(1):16–25.

    Article  PubMed  CAS  Google Scholar 

  22. Debruyne PR, Witek M, Gong L, Birbe R, Chervoneva I, Jin T, et al. Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells. Gastroenterology. 2006;130(4):1191–1206.

    Article  PubMed  CAS  Google Scholar 

  23. Moons LMG, Bax DA, Kuipers EJ, Van Dekken H, Haringsma J, Van Vliet AHM, et al. The homeodomain protein CDX2 is an early marker of Barrett’s oesophagus. J Clin Pathol. 2004;57(10):1063–1068.

    Article  PubMed  CAS  Google Scholar 

  24. Wong NACS, Wilding J, Bartlett S, Liu Y, Warren BF, Piris J, et al. CDX1 is an important molecular mediator of Barrett’s metaplasia. Proc Natl Acad Sci USA. 2005;102(21):7565–7570.

    Article  PubMed  CAS  Google Scholar 

  25. Rahman FB, Kadowaki Y, Ishihara S, Tobita H, Imaoka H, Fukuhara H, et al. Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells. Lab Invest. 2010;90(7):1033–1048.

    Article  PubMed  CAS  Google Scholar 

  26. Kerkhof M, Bax DA, Moons LMG, van Vuuren AJ, Van Dekken H, Steyerberg EW, et al. Does CDX2 expression predict Barrett’s metaplasia in oesophageal columnar epithelium without goblet cells? Aliment Pharmacol Ther. 2006;24(11–12):1613–1621.

    Article  PubMed  CAS  Google Scholar 

  27. Abdalla SI, Lao-Sirieix P, Novelli MR, Lovat LB, Sanderson IR, Fitzgerald RC. Gastrin-induced cyclooxygenase-2 expression in Barrett’s carcinogenesis. Clin Cancer Res. 2004;10(14):4784–4792.

    Article  PubMed  CAS  Google Scholar 

  28. Vallb Ohmer D, DeMeester SR, Oh DS, Banki F, Kuramochi H, Shimizu D, et al. Antireflux surgery normalizes cyclooxygenase-2 expression in squamous epithelium of the distal esophagus. Am J Gastroenterol. 2006;101(7):1458–1466.

    Article  Google Scholar 

  29. Ferguson HR, Wild CP, Anderson LA, Murphy SJ, Johnston BT, Murray LJ, 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. 2008;17(3):727–731.

    Article  PubMed  CAS  Google Scholar 

  30. Kuramochi H, Vallb Ohmer D, Uchida K, Schneider S, Hamoui N, Shimizu D, et al. Quantitative, tissue-specific analysis of cyclooxygenase gene expression in the pathogenesis of Barrett’s adenocarcinoma. J Gastrointest Surg. 2004;8(8):1007-16. discussion 1016–7.

    Article  PubMed  Google Scholar 

  31. van der Woude CJ, Jansen PLM, Tiebosch ATGM, Beuving A, Homan M, Kleibeuker JH, et al. Expression of apoptosis-related proteins in Barrett’s metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype. Hum Pathol. 2002;33(7):686–692.

    Article  PubMed  CAS  Google Scholar 

  32. Villanacci V, Rossi E, Zambelli C, Galletti A, Cestari R, Missale G, et al. COX-2, CDX2, and CDC2 immunohistochemical assessment for dysplasia-carcinoma progression in Barrett’s esophagus. Dig Liver Dis. 2007;39(4):305–311.

    Article  PubMed  CAS  Google Scholar 

  33. Arber N, Lightdale C, Rotterdam H, Han KH, Sgambato A, Yap E, et al. Increased expression of the cyclin D1 gene in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev. 1996;5(6):457–459.

    PubMed  CAS  Google Scholar 

  34. Izzo JG, Wu T-T, Wu X, Ensor J, Luthra R, Pan J, et al. Cyclin D1 guanine/adenine 870 polymorphism with altered protein expression is associated with genomic instability and aggressive clinical biology of esophageal adenocarcinoma. J Clin Oncol. 2007;25(6): 698–707.

    Article  PubMed  CAS  Google Scholar 

  35. Avissar NE, Toia L, Hu Y, Watson TJ, Jones C, Raymond DP, et al. Bile acid alone, or in combination with acid, induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR). J Gastrointest Surg. 2009;13(2):212–222.

    Article  PubMed  Google Scholar 

  36. Cronin J, McAdam E, Danikas A, Tselepis C, Griffiths P, Baxter J, et al. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett’s esophagus (BE). Am J Gastroenterol. 2011;106(1):46–56.

    Article  PubMed  CAS  Google Scholar 

  37. al-Kasspooles M, Moore JH, Orringer MB, Beer DG. Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas. Int J Cancer. 1993;54(2):213–219.

    Article  PubMed  CAS  Google Scholar 

  38. Miller CT, Moy JR, Lin L, Schipper M, Normolle D, Brenner DE, et al. Gene amplification in esophageal adenocarcinomas and Barrett’s with high-grade dysplasia. Clin Cancer Res. 2003;9(13):4819–4825.

    PubMed  CAS  Google Scholar 

  39. Sommerer F, Vieth M, Markwarth A, Rohrich K, Vomschloss S, May A, et al. Mutations of BRAF and KRAS2 in the development of Barrett’s adenocarcinoma. Oncogene. 2004;23(2):554–558.

    Article  PubMed  CAS  Google Scholar 

  40. Jankowski J, Coghill G, Hopwood D, Wormsley KG. Oncogenes and onco-suppressor gene in adenocarcinoma of the oesophagus. Gut. 1992;33(8):1033–1038.

    Article  PubMed  CAS  Google Scholar 

  41. Walch A, Specht K, Bink K, Zitzelsberger H, Braselmann H, Bauer M, et al. Her-2/neu gene amplification, elevated mRNA expression, and protein overexpression in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett’s esophagus. Lab Invest. 2001;81(6):791–801.

    Article  PubMed  CAS  Google Scholar 

  42. Walch A, Bink K, Gais P, Stangl S, Hutzler P, Aubele M, et al. Evaluation of c-erbB-2 overexpression and Her-2/neu gene copy number heterogeneity in Barrett’s adenocarcinoma. Anal Cell Pathol. 2000;20(1):25–32.

    PubMed  CAS  Google Scholar 

  43. Brien TP, Odze RD, Sheehan CE, McKenna BJ, Ross JS. HER-2/neu gene amplification by FISH predicts poor survival in Barrett’s esophagus-associated adenocarcinoma. Hum Pathol. 2000;31(1):35–39.

    Article  PubMed  CAS  Google Scholar 

  44. Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet. 2010;376(9742):687–697.

    Article  CAS  Google Scholar 

  45. Hu Y, Bandla S, Godfrey TE, Tan D, Luketich JD, Pennathur A, et al. HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma. Mod Pathol. 2011;24(7):899–907.

    Article  PubMed  CAS  Google Scholar 

  46. Muzeau F, Flejou JF, Belghiti J, Thomas G, Hamelin R. Infrequent microsatellite instability in oesophageal cancers. Br J Cancer. 1997;75(9):1336–1339.

    Article  PubMed  CAS  Google Scholar 

  47. Meltzer SJ, Yin J, Manin B, Rhyu MG, Cottrell J, Hudson E, et al. Microsatellite instability occurs frequently and in both diploid and aneuploid cell populations of Barrett’s-associated esophageal adenocarcinomas. Cancer Res. 1994;54(13):3379–3382.

    PubMed  CAS  Google Scholar 

  48. Keller G, Rotter M, Vogelsang H, Bischoff P, Becker KF, Mueller J, et al. Microsatellite instability in adenocarcinomas of the upper gastrointestinal tract. Relation to clinicopathological data and family history. Am J Pathol. 1995;147(3):593–600.

    PubMed  CAS  Google Scholar 

  49. Gleeson CM, Sloan JM, McGuigan JA, Ritchie AJ, Weber JL, Russell SE. Ubiquitous somatic alterations at microsatellite alleles occur infrequently in Barrett’s-associated esophageal adenocarcinoma. Cancer Res. 1996;56(2):259–263.

    PubMed  CAS  Google Scholar 

  50. Gu J, Ajani JA, Hawk ET, Ye Y, Lee JH, Bhutani MS, et al. Genome-wide catalogue of chromosomal aberrations in Barrett’s esophagus and esophageal adenocarcinoma: a high-density single nucleotide polymorphism array analysis. Cancer Prev Res (Phila). 2010;3(9):1176–1186.

    Article  CAS  Google Scholar 

  51. Doak SH, Jenkins GJS, Parry EM, D’Souza FR, Griffiths AP, Toffazal N, et al. Chromosome 4 hyperploidy represents an early genetic aberration in premalignant Barrett’s oesophagus. Gut. 2003;52(5):623–628.

    Article  PubMed  CAS  Google Scholar 

  52. Gaj P, Mikula M, Wyrwicz LS, Regula J, Ostrowski J. Barrett’s esophagus associates with a variant of IL23R gene. Acta Biochim Pol. 2008;55(2):365–369.

    PubMed  CAS  Google Scholar 

  53. Moons LMG, Kusters JG, van Delft JHM, Kuipers EJ, Gottschalk R, Geldof H, et al. A pro-inflammatory genotype predisposes to Barrett’s esophagus. Carcinogenesis. 2008;29(5):926–931.

    Article  PubMed  CAS  Google Scholar 

  54. Gough MD, Ackroyd R, Majeed AW, Bird NC. Prediction of malignant potential in reflux disease: are cytokine polymorphisms important? Am J Gastroenterol. 2005;100(5):1012–1018.

    Article  PubMed  CAS  Google Scholar 

  55. Dvorakova K, Payne CM, Ramsey L, Holubec H, Sampliner R, Dominguez J, et al. Increased expression and secretion of interleukin-6 in patients with Barrett’s esophagus. Clin Cancer Res. 2004;10(6):2020–2028.

    Article  PubMed  CAS  Google Scholar 

  56. Oh DS, DeMeester SR, Vallbohmer D, Mori R, Kuramochi H, Hagen JA, et al. Reduction of interleukin 8 gene expression in reflux esophagitis and Barrett’s esophagus with antireflux surgery. Arch Surg. 2007;142(6):554–9. discussion 559–60.

    Article  PubMed  CAS  Google Scholar 

  57. Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, Saeed IT, Burnham WR, Farthing MJG. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut. 2002;50(4):451–459.

    Article  PubMed  CAS  Google Scholar 

  58. Zhong Y-QQ, Lin Y, Xu Z. Expression of IFN-γ and IL-4 in the esophageal mucosa of patients with Reflux Esophagitis and Barrett’s Esophagus and their relationship with endoscopic and histologic grading. Dig Dis Sci. 2011;56:2865–70.

    Article  PubMed  CAS  Google Scholar 

  59. Eads CA, Lord RV, Kurumboor SK, Wickramasinghe K, Skinner ML, Long TI, et al. Fields of aberrant CpG island hypermethylation in Barrett’s esophagus and associated adenocarcinoma. Cancer Res. 2000;60(18):5021–5026.

    PubMed  CAS  Google Scholar 

  60. Kawakami K, Brabender J, Lord RV, Groshen S, Greenwald BD, Krasna MJ, et al. Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst. 2000;92(22):1805–1811.

    Article  PubMed  CAS  Google Scholar 

  61. Clement G, Braunschweig R, Pasquier N, Bosman FT, Benhattar J. Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett’s esophagus. Oncogene. 2006;25(21):3084–3092.

    Article  PubMed  CAS  Google Scholar 

  62. Clement G, Braunschweig R, Pasquier N, Bosman FT, Benhattar J. Methylation of APC, TIMP3, and TERT: a new predictive marker to distinguish Barrett’s oesophagus patients at risk for malignant transformation. J Pathol. 2006;208(1):100–107.

    Article  PubMed  CAS  Google Scholar 

  63. Clement G, Guilleret I, He B, Yagui-Beltran A, Lin Y-CC, You L, et al. Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett’s esophagus. Cancer Sci. 2008;99(1):46–53.

    PubMed  CAS  Google Scholar 

  64. Lee O-JJ, Schneider-Stock R, McChesney PA, Kuester D, Roessner A, Vieth M, et al. Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett’s tumorigenesis. Neoplasia. 2005;7(9):854–861.

    Article  PubMed  CAS  Google Scholar 

  65. Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y, et al. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett’s-associated neoplastic progression and predicts progression risk. Oncogene. 2005;24(25):4138–4148.

    PubMed  CAS  Google Scholar 

  66. Hamilton JP, Sato F, Jin Z, Greenwald BD, Ito T, Mori Y, et al. Reprimo methylation is a potential biomarker of Barrett’s-Associated esophageal neoplastic progression. Clin Cancer Res. 2006;12(22):6637–6642.

    Article  PubMed  CAS  Google Scholar 

  67. Onwuegbusi BA, Aitchison A, Chin S-FF, Kranjac T, Mills I, Huang Y, et al. Impaired transforming growth factor beta signalling in Barrett’s carcinogenesis due to frequent SMAD4 inactivation. Gut. 2006;55(6):764–774.

    Article  PubMed  CAS  Google Scholar 

  68. Tischoff I, Hengge UR, Vieth M, Ell C, Stolte M, Weber A, et al. Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma. Gut. 2007;56(8):1047–1053.

    Article  PubMed  CAS  Google Scholar 

  69. Kuester D, Dar AA, Moskaluk CC, Krueger S, Meyer F, Hartig R, et al. Early involvement of death-associated protein kinase promoter hypermethylation in the carcinogenesis of Barrett’s esophageal adenocarcinoma and its association with clinical progression. Neoplasia. 2007;9(3):236–245.

    Article  PubMed  CAS  Google Scholar 

  70. Kuester D, El-Rifai W, Peng D, Ruemmele P, Kroeckel I, Peters B, et al. Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett’s esophagus. Cancer Lett. 2009;275(1):117–126.

    Article  PubMed  CAS  Google Scholar 

  71. Abdelatif OM, Chandler FW, Mills LR, McGuire BS, Pantazis CG, Barrett JM. Differential expression of c-myc and H-ras oncogenes in Barrett’s epithelium. A study using colorimetric in situ hybridization. Arch Pathol Lab Med. 1991;115(9):880–885.

    PubMed  CAS  Google Scholar 

  72. Schmidt MK, Meurer L, Volkweis BS, Edelweiss MI, Schirmer CC, Kruel CDP, et al. c-Myc overexpression is strongly associated with metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Dis Esophagus. 2007;20(3):212–216.

    Article  PubMed  CAS  Google Scholar 

  73. Sorsdahl K, Casson AG, Troster M, Van Meyel D, Inculet R, Chambers AF. p53 and ras gene expression in human esophageal cancer and Barrett’s epithelium: a prospective study. Cancer Detect Prev. 1994;18(3):179–185.

    PubMed  CAS  Google Scholar 

  74. Trautmann B, Wittekind C, Strobel D, Meixner H, Keymling J, Gossner L, et al. K-ras point mutations are rare events in premalignant forms of Barrett’s oesophagus. Eur J Gastroenterol Hepatol. 1996;8(8):799–804.

    PubMed  CAS  Google Scholar 

  75. Barrett MT, Sanchez CA, Galipeau PC, Neshat K, Emond M, Reid BJ. Allelic loss of 9p21 and mutation of the CDKN2/p16 gene develop as early lesions during neoplastic progression in Barrett’s esophagus. Oncogene. 1996;13(9):1867–1873.

    PubMed  CAS  Google Scholar 

  76. Paulson TG, Galipeau PC, Xu L, Kissel HD, Li X, Blount PL, et al. p16 mutation spectrum in the premalignant condition Barrett’s esophagus. PLoS One. 2008;3(11):e3809.

    Article  PubMed  CAS  Google Scholar 

  77. Wong DJ, Barrett MT, Stoger R, Emond MJ, Reid BJ. p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res. 1997;57(13):2619–2622.

    PubMed  CAS  Google Scholar 

  78. Bian Y-SS, Osterheld M-CC, Fontolliet C, Bosman FT, Benhattar J. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s esophagus. Gastroenterology. 2002;122(4):1113–1121.

    Article  PubMed  CAS  Google Scholar 

  79. Klump B, Hsieh CJ, Holzmann K, Gregor M, Porschen R. Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett’s esophagus. Gastroenterology. 1998;115(6):1381–1386.

    Article  PubMed  CAS  Google Scholar 

  80. Wong DJ, Paulson TG, Prevo LJ, Galipeau PC, Longton G, Blount PL, et al. p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett’s metaplastic epithelium. Cancer Res. 2001;61(22):8284–8289.

    PubMed  CAS  Google Scholar 

  81. Maley CC, Galipeau PC, Li X, Sanchez CA, Paulson TG, Reid BJ. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett’s esophagus. Cancer Res. 2004;64(10):3414–3427.

    Article  PubMed  CAS  Google Scholar 

  82. Leedham SJ, Preston SL, McDonald SAC, Elia G, Bhandari P, Poller D, et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus. Gut. 2008;57(8):1041–1048.

    Article  PubMed  CAS  Google Scholar 

  83. Casson AG, Mukhopadhyay T, Cleary KR, Ro JY, Levin B, Roth JA. p53 gene mutations in Barrett’s epithelium and esophageal cancer. Cancer Res. 1991;51(16):4495–4499.

    PubMed  CAS  Google Scholar 

  84. Blount PL, Ramel S, Raskind WH, Haggitt RC, Sanchez CA, Dean PJ, et al. 17p allelic deletions and p53 protein overexpression in Barrett’s adenocarcinoma. Cancer Res. 1991;51(20):5482–5486.

    PubMed  CAS  Google Scholar 

  85. Hamelin R, Flejou JF, Muzeau F, Potet F, Laurent-Puig P, Fekete F, et al. TP53 gene mutations and p53 protein immunoreactivity in malignant and premalignant Barrett’s esophagus. Gastroenterology. 1994;107(4):1012–1018.

    PubMed  CAS  Google Scholar 

  86. Ramel S, Reid BJ, Sanchez CA, Blount PL, Levine DS, Neshat K, et al. Evaluation of p53 protein expression in Barrett’s esophagus by two-parameter flow cytometry. Gastroenterology. 1992;102(4 Pt 1):1220–1228.

    PubMed  CAS  Google Scholar 

  87. Younes M, Lebovitz RM, Lechago LV, Lechago J. p53 protein accumulation in Barrett’s metaplasia, dysplasia, and carcinoma: a follow-up study. Gastroenterology. 1993;105(6):1637–1642.

    PubMed  CAS  Google Scholar 

  88. Younes M, Ertan A, Lechago LV, Somoano JR, Lechago J. p53 Protein accumulation is a specific marker of malignant potential in Barrett’s metaplasia. Dig Dis Sci. 1997;42(4):697–701.

    Article  PubMed  CAS  Google Scholar 

  89. Weston AP, Banerjee SK, Sharma P, Tran TM, Richards R, Cherian R. p53 protein overexpression in low grade dysplasia (LGD) in Barrett’s esophagus: immunohistochemical marker predictive of progression. Am J Gastroenterol. 2001;96(5):1355–1362.

    Article  PubMed  CAS  Google Scholar 

  90. Blount PL, Galipeau PC, Sanchez CA, Neshat K, Levine DS, Yin J, et al. 17p allelic losses in diploid cells of patients with Barrett’s esophagus who develop aneuploidy. Cancer Res. 1994;54(9):2292–2295.

    PubMed  CAS  Google Scholar 

  91. Neshat K, Sanchez CA, Galipeau PC, Blount PL, Levine DS, Joslyn G, et al. p53 mutations in Barrett’s adenocarcinoma and high-grade dysplasia. Gastroenterology. 1994;106(6):1589–1595.

    PubMed  CAS  Google Scholar 

  92. Coggi G, Bosari S, Roncalli M, Graziani D, Bossi P, Viale G, et al. p53 protein accumulation and p53 gene mutation in esophageal carcinoma. A molecular and immunohistochemical study with clinicopathologic correlations. Cancer. 1997;79(3):425–432.

    Article  PubMed  CAS  Google Scholar 

  93. Doak SH, Jenkins GJS, Parry EM, Griffiths AP, Shah V, Baxter JN, et al. Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma. Br J Cancer. 2003;89(9):1729–1735.

    Article  PubMed  CAS  Google Scholar 

  94. Vaninetti NM, Geldenhuys L, Porter GA, Risch H, Hainaut P, Guernsey DL, et al. Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett’s esophagus and esophageal adenocarcinoma. Mol Carcinog. 2008;47(4):275–285.

    Article  PubMed  CAS  Google Scholar 

  95. Younes M, Lechago J, Chakraborty S, Ostrowski M, Bridges M, Meriano F, et al. Relationship between dysplasia, p53 protein accumulation, DNA ploidy, and Glut1 overexpression in Barrett metaplasia. Scand J Gastroenterol. 2000;35(2):131–137.

    Article  PubMed  CAS  Google Scholar 

  96. Reid BJ, Haggitt RC, Rubin CE, Rabinovitch PS. Barrett’s esophagus. Correlation between flow cytometry and histology in detection of patients at risk for adenocarcinoma. Gastroenterology. 1987;93(1):1–11.

    PubMed  CAS  Google Scholar 

  97. Robaszkiewicz M, Hardy E, Volant A, Nousbaum JB, Cauvin JM, Calament G, et al. Flow cytometric analysis of cellular DNA content in Barret’s esophagus. A study of 66 cases. Gastroenterol Clin Biol. 1991;15(10):703–710.

    PubMed  CAS  Google Scholar 

  98. Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS. Flow-cytometric and histological progression to malignancy in Barrett’s esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology. 1992;102(4 Pt 1):1212–1219.

    PubMed  CAS  Google Scholar 

  99. Menke-Pluymers MB, Mulder AH, Hop WC, van Blankenstein M, Tilanus HW. Dysplasia and aneuploidy as markers of malignant degeneration in Barrett’s oesophagus. The Rotterdam Oesophageal Tumour Study Group. Gut. 1994;35(10):1348–1351.

    Article  PubMed  CAS  Google Scholar 

  100. Giménez A, Minguela A, Parrilla P, Bermejo J, Pérez D, Molina J, et al. Flow cytometric DNA analysis and p53 protein expression show a good correlation with histologic findings in patients with Barrett’s esophagus. Cancer. 1998;83(4):641–651.

    Article  PubMed  Google Scholar 

  101. Maley CC, Galipeau PC, Li X, Sanchez CA, Paulson TG, Blount PL, et al. The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res. 2004;64(20):7629–7633.

    Article  PubMed  CAS  Google Scholar 

  102. Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD, et al. NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med. 2007;4(2):e67.

    Article  PubMed  CAS  Google Scholar 

  103. Wang JS, Guo M, Montgomery EA, Thompson RE, Cosby H, Hicks L, et al. DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett’s esophagus. Am J Gastroenterol. 2009;104(9):2153–2160.

    Article  PubMed  CAS  Google Scholar 

  104. Jin Z, Cheng Y, Gu W, Zheng Y, Sato F, Mori Y, et al. A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett’s esophagus. Cancer Res. 2009;69(10):4112–4115.

    Article  PubMed  CAS  Google Scholar 

  105. Yang H, Gu J, Wang KK, Zhang W, Xing J, Chen Z, et al. MicroRNA expression signatures in Barrett’s esophagus and esophageal adenocarcinoma. Clin Cancer Res. 2009;15(18): 5744–5752.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, University of Texas Medical School at Houston, 6413 Fannin, MSB 2.270, Houston, TX, 77030, USA

    Mamoun Younes M.D.

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  1. Department of Pathology & Cell Biology, Columbia University, New York, 10032, New York, USA

    Antonia R. Sepulveda

  2. Division of Gastroenterology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    John P. Lynch

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Younes, M. (2013). Molecular Pathology of Barrett’s Metaplasia and Esophageal Adenocarcinoma. In: Sepulveda, A., Lynch, J. (eds) Molecular Pathology of Neoplastic Gastrointestinal Diseases. Molecular Pathology Library, vol 7. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-6015-2_3

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