Barrett's Esophagus: Can Biomarkers Predict Progression to Malignancy?

Iris Tischoff; Andrea Tannapfel

Expert Rev Gastroenterol Hepatol. 2008;2(5):653-663.

Five-year View

Clinical Features

In the era of technical know-how, the development and improvement of high-resolution endoscopic imaging techniques will improve the assessment of the macroscopic appearance of Barrett's lesions and aid the early detection of neoplastic lesions. Nonetheless, biopsies will remain necessary throughout the next 5 years. In the case of endoscopic therapy, new techniques will improve endoscopical resection and minimize the remaining Barrett's segments.

Molecular Features

Focusing on the epigenetic pathway, DNA methylation and histone modifications are both reversible events. It was demonstrated, in vitro and in vivo, that re-expression of epigenetically silenced tumor-suppressor genes is possible by using demethylating (e.g., 5´-AZA and Zebularine) and histone-modifying agents (e.g., the histone deacetylase inhibitor Trichostatin). Similar to the manner in which Trichostatin has become an option for the treatment of myelodysplastic syndrome, re-expression of epigenetically silenced tumor-suppressor genes may also become an approach in the chemotherapeutic treatment of EA over the next few years. Modulation of the epigenetically involved pathways by using small molecules that are more specific may become another possible aspect of chemotherapy. However, further investigations in clinical trials are necessary to prove and integrate epigenetic pathway-modulating agents.

Another point of interest is the role of miRNAs. Recent studies have suggested that they can act as both tumor-suppressor genes and oncogenes. Furthermore, miRNA expression profiles can classify tissue and tumor types, for example, distinguishing benign from malignant tissue. Identifying specific miRNA patterns in Barrett's lesions may help to detect the BE and dysplasia with more progressive potential and help to distinguish low-risk from high-risk patients. Another potential aspect could be the identification of new predictive biomarkers in the coming years and the improvement of understanding the development of malignant transformation.

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Papers of special note have been highlighted as: • of interest •• of considerable interest

Chow WH, Blot WJ, Vaughan TL et al. Body mass index and risk of adenocarcinomas of the oesophagus and gastric cardia. J. Natl Cancer Inst. 90(2), 150-155 (1998).
Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol and tobacco as risk factors for cancers of the oesophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 4(2), 85-92 (1995).
Yanagai M, Keller G, Mueller J et al. Comparison of loss of heterozygosity and microsatellite instability in adenocarcinomas of the distal esophagus and proximal stomach. Virchows Arch. 437(6), 605-610 (2000).
Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 54(5), 710-717 (2005).
Ronkainen J, Aro P, Storskubb T et al. Prevalence of Barrett's esophagus in the general population: an endoscopic study. Gastroenterology 129(6), 1825-1831 (2005).
Zagorowicz E, Jankowski J. Molecular changes in the progression of Barrett's oesophagus. Postgrad. Med. J. 83(982), 529-535 (2007).
•Systematic review of molecular biomarkers, regarding the ASPECT study in the UK.
Sommerer F, Vieth M, Markwarth A et al. Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma. Oncogene 23(2), 554-558 (2004).
Jankowski J, Provenzale D, Moayyedi P. Esophageal adenocarcinoma arising from Barrett's metaplasia has regional variations in the west. Gastroenterology 122(2), 588-590 (2002).
Haggitt RC. Barrett's esophagus, dysplasia and adenocarcinoma. Hum. Pathol. 25(2), 982-993 (1994).
Sharma P, Marcon N, Wani S et al. Non-biopsy detection of intestinal metaplasia and dysplasia in Barrett's esophagus: a prospective multicenter study. Endoscopy 38(12), 1206-1212 (2006).
Nilsson J, Skobe V, Johansson J, Willen R, Johnsson F. Screening for esophageal adenocarcinoma: an evaluation of a surveillance program for columnar metaplasia of esophagus. Scand. J. Gastroenterol. 35(1), 10-16 (2000).
Biomarkers definitions working group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69(3), 89-95 (2001).
Williams LJ, Guernsey DL, Casson AG. Biomarkers in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Curr. Oncol. 13(1), 33-43 (2006).
•Comprehensive review of molecular biomarkers considering the definition of biomarkers by the biomarkers definition working group.
Pepe MS, Etzioni R, Feng Z et al. Phases of biomarker development for early detection of cancer. J. Natl Cancer Inst. 93(14), 1054-1061 (2001).
Cameron AJ, Ott BJ, Payne WS. The incidence of adenocarcinoma in columnar-lined (Barrett's) esophagus. N. Engl. J. Med. 313 (14), 857-859 (1985).
Shaheen N, Ransohoff DF. Gastroesophageal reflux, Barrett's esophagus and esophageal cancer. JAMA 287(14), 1972-1981 (2002).
Pech O, Vieth M, Schmitz D et al. Conclusions from the histological diagnosis of low-grade intraepithelial neoplasia in Barrett's oesophagus. Scand. J. Gastroenterol. 42(6), 682-688 (2007).
Barr H, Kendall C, Bazant-Hegemark F, Moayyedi P, Shetty G, Stone N. Endocsopic screening and surveillance for Barrett's esophagus. MedGenMed 8(2), 88 (2006).
Pohl H, Koch M, Khalifa A et al. Evaluation of endoscopy in the surveillance of patients with Barrett's esophagus. Endoscopy 39(6), 492-496 (2007).
Montgomery E, Bronner MP, Goldblum JR et al. Reproducibility of the diagnosis of dysplasia in Barrett's esophagus: a reaffirmation. Hum. Pathol. 32(4), 368-387 (2001).
Skacel M, Petras RE, Gramlich TL, Sigel JE, Richter JE, Goldblum JR. The diagnosis of low grade dysplasia in Barrett's esophagus and its implications for disease progression. Am. J. Gastroenterol. 95(12), 3383-3387 (2000).
Pech O, Gossner L, Manner H et al. Prospective evaluation of the macroscopic types and lesions of early Barrett's neoplasia in 380 lesions. Endoscopy 39(7), 588-593 (2007).
Vaughan TL, Kristal AR, Blount PL et al. Nonsteroidal anti-inflammatory drug use, body mass index, and anthropometry in relation to genetic and flow cytometric abnormalities in Barrett's esophagus. Cancer Epidemiol. Biomarkers Prev. 11(8), 745-752 (2002).
Merry AHH, Schouten LJ, Goldbohm RA, van den Brandt PA. Body mass index, height and risk of adenocarcinoma of the oesophagus and gastric cardia: a prospective cohort study. Gut 56(11), 1503-1511 (2007).
Gatenby PAC, Caygill CPJ, Ramus JR et al. Short segment columnar-lined oesophagus: an underestimated cancer risk? A large cohort study of the relationship between Barrett's colunar-lined oesophagus segment length and adenocarcinoma risk. Eur. J. Gastroenterol. Hepatol. 19(11), 969-975 (2007).
Anandasabapathy SH, Jhamb J, Davilla M, Wei C, Morris J, Bresalier R. Clinical and endoscopic factors predict higher pathologic grades of Barrett dysplasia. Cancer 109(4), 668-674 (2007).
Dong LM, Kristal AR, Peters U et al. Dietary supplement use and risk of neoplastic progression in esophageal adenocarcinoma: a prospective study. Nutr. Cancer. 60(1), 39-48 (2008).
Rudolph RE, Vaughan TL, Kristal AR et al. Serum selenium levels in relation to markers of neoplastic progression among persons with Barrett's esophagus. J. Natl Cancer Inst. 95(10), 750-757 (2003).
Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD. NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med. 4(2), E67 (2007).
Sanz-Ortega J, Hernández S, Saez MC et al. 3p21, 5q21, 9p21 and 17p13.1 allelic deletions are potential markers of individuals with a high risk of developing adenocarcinoma in Barrett's epithelium without dysplasia. Hepatogastroenterology 50(50), 404-407 (2003).
Helm J, Enkemann SA, Coppola D, Barthel JS, Kelley ST, Yeatman TJ. Dedifferentiation precedes invasion in the progression from Barrett's metaplasia to esophageal adenocarcinoma. Clin. Cancer Res. 11(7), 2478-2485 (2005).
Chaves P, Crespo M, Ribeiro C et al. Chromosomal analysis of Barrett's cells: demonstration of instability and detection of the metaplastic lineage involved. Mod. Pathol. 20(7), 788-796 (2007).
Wijnhoven BP, Tilanus HW, Dinjens WNM. Molecular biology of Barrett's adenocarcinoma. Ann. Surg. 233(3), 322-337 (2001).
Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett's esophagus. Am. J. Gastroenterol. 95(7), 1669-1676 (2000).
Kim NW, Piatyszek MA, Prowse KR et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266 (5193), 2011-2015 (1994).
Fitzgerald RC. Barrett's oesophagus and oesophageal adenocacinoma: how does acid interfere with cell proliferation and differentiation? Gut 54 (12), 21-26 (2005).
•Systematic review regarding environmental factors and molecular changes.
Barclay JY, Morris A, Nwokolo CHU. Telomerase, hTERT and splice variants in Barrett's oesophagus and oesophageal adenocarcinoma. Eur. J. Gatroenterol. Hepatol. 17(2), 221-227 (2005).
Gertler R, Doll D, Maak M, Feith M, Rosenberg R. Telomere length and telomerase subunits as diagnostic and prognostic biomarkers in Barrett carcinoma. Cancer 112(10), 2173-2180 (2008).
Risques RA, Vaughan TL, Li X et al. Leukocyte telomere length predicts cancer risk in Barrett's esophagus. Cancer Epidemiol. Biomarkers Prev. 16(12), 2649-2655 (2008).
Finley JC, Reid BJ, Odze RD et al. Chromosomal instability in Barrett's esophagus is related to telomere shortening. Cancer Epidemiol. Biomarkers Prev. 15(8), 1451-1457 (2006).
Ouatu-Luscar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression. Gastroenterology 117(2), 327-335 (1999).
Kerkhof M, Steverberg EW, Kusters JG et al. Aneuploidy and high expression of p53 and Ki67 is associated with neoplastic progression in Barrett's esophagus. Cancer Biomark. 1(4), 1-10 (2008).
Halm U, Tannapfel A, Breitung B, Breidert M, Wittekind CH, Moessner J. Apoptosis and cell proliferation in the metaplasia-dysplasia-carcinoma-sequence of Barrett's esophagus. Hepatogastroenterology 47 (34), 962 - 966 (2000).
Sirieix P, O'Donovan M, Brown J, Save V, Coleman N, Fitzgerald RC. 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(7), 2560-2566 (2003).
Going JJ, Keith WN, Neilson J, Stoeber K, Stuart RC, Williams GH. Aberrant expression of minichromosome maintance proteins 2 and 5, and Ki-67 in dysplastic squamous epithelium and Barrett's mucosa. Gut 50(3), 373-377 (2002).
Tannapfel A. Molecular findings in Barrett's epithelium. Dig. Dis. 22(2), 126-133 (2004).
Van der Woude CJ, Jansen PLM, Tiebosch ATG et al. Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype. Hum. Pathol. 33(7), 686-691 (2002).
Conio M, Lapertosa G, Blanchi S, Filiberti R. Barrett's esophagus: an update. Crit. Rev. Oncol. Hematol. 46(2), 187-206 (2003).
Spechler SJ. Clinical practice: Barrett's esophagus. N. Engl. J. Med. 346(11), 836-842 (2002).
Goldblum JR. Barrett's esophagus and Barrett's-related dysplasia. Mod. Pathol. 16(4), 316-324 (2003).
Casson AG, Evans SC, Gillis A et al. Clinical implications of p53 tumor suppressor gene mutation and protein expression in esophageal adenocarcinomas : results of a ten-year prospective study. J. Thorac. Cardiovasc. Surg. 125(5), 1121-1131 (2003).
Song SH, Guha S, Liu K, Buttar NS, Breaslier RS. COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett's oesophagus and oesophageal adenocarcinoma. Gut 56(11), 1512-1521 (2007).
Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased expression of inducible nitric oxidade synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res. 58(14), 2929-2934 (1998).
Morris CD, Armstrong GR, Bigley G, Green H, Attwood SE. Cylooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma-sequence. Am. J. Gastroenterol. 96(4), 990-996 (2001).
Von Rahden BHA, Stein HJ, Pühringer-Oppermann F, Sarbia M. c-myc amplification is frequent in esophageal adenocarcinoma and correlated with upregulation of VEGF-A expression. Neoplasia 8(9), 702-702 (2006).
Auvinen MI, Sihvo EIT, Ruohtula T et al. Incipient angiogenesis in Barrett's epithelium and lymphangiogenesis in Barrett's adenocarcinoma. J. Clin. Oncol. 20(13), 2971-2979 (2002).
Möbius C, Stein HJ, Becker I et al. Vascular endothelial growth factor expression and neovascularization in Barrett's carcinoma. World J. Surg. 28(7), 675-679 (2004).
Peters CJ, Fitzgerald RC. Systematic review: the application of molecular pathogenesis to prevention and treatment of oesophageal adenocarcinoma. Aliment. Pharmacol. Ther. 25(11), 1253-1269 (2007).
•Interesting review discussing molecular alterations and their possible clinical application in prevention and treatment.
Freund JN, Domon-Cell C, Kedinger M, Duluc I. The Cdx-1 and Cdx-2 homeobox genes in the intestine. Biochem. Cell Biol. 76(6), 957-969 (1998).
Burnat G, Rau T, Elshimi E, Hahn EG, Konturek PC. Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett's esophageal mucosa and adenocarcinoma cell line. Scand. J. Gastroenterol. 42(12), 1460-1465 (2007).
Hu Y, Williams VA, Gellersen O, Jones C, Watson TJ, Peters JH. The pathogenesis of Barrett's esophagus: secondary bile acids upregulate intestinal differentiation factor CDX2 expression in esophagus cells. J. Gastrointest. Surg. 11(7), 827-834 (2007).
Wong NA, Wilding J, Bartlett S et al. CDX1 is an important molecular mediator of Barrett's metaplasia. Proc. Natl Acad. Sci. USA 102(21), 7565-7570 (2005).
Vallbohmer D, DeMeester SR, Peters JH et al. CDX-2 expression in squamous and metaplastic columnar epithelia of the esophagus. Dis. Esophagus 19(4), 260-266 (2006).
Debryune PR, Witek M, Gong L et al. Bile acids induce ectopic expression of intestinal guanylyl cyclase C through NF-κB and Cdx2 in human esophageal cells. Gastroenterology 130(4), 1191-1206 (2006).
Lord RV, Brabender J, Wickramasinghe K et al. Increased CDX2 and decreased PITX1 homeobox gene expression in Barrett's esophagus and Barrett's-associated adenocarcinoma. Surgery 138(5), 924-931 (2005).
Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat. Rev. Cancer 6(4), 259-269 (2006).
Lu J, Getz G, Miska EA et al. MicroRNA expression profiles classify human cancers. Nature 435(7043), 834-838 (2005).
Feber A, Xi L, Luketich JD, Pennathur A et al. MicroRNA expression profiles in esophageal cancer. J. Thorac. Cardiovasc. Surg. 135(2), 255-260 (2008)
Peng D, Sheta EA, Powell SM et al. Alterations in Barrett's-related adenocarcinomas: a proteomic approach. Int. J. Cancer 122(6), 1303-1310 (2008).
Razvi MH, Peng D, Dar AA et al. Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: serial analysis of gene expression. Genes Chromosomes Cancer 46(10), 914-928 (2007).
Greenawalt DM, Duong C, Smyth GK et al. Gene expression profiling of esophageal cancer: comparative analysis of Barrett's esophagus, adenocarcinoma, and squamous cell carcinoma. Int. J. Cancer 120(9), 1914-1921 (2007).
Ehrlich M. DNA hypomethylation in cancer. In: DNA Alterations in Cancer: Genetic and Epigenetic Changes. Ehrlich M (Ed.). Natick: Eaton Publishing, MA, USA 273-291 (2000).
Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Z. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Oncogene 24(25), 4138-4148 (2005).
Clément G, Braunschweig R, Pasquier N, Bosman FT, Benhattar J. Methylation of APC, TIMP3, and TERT: a new predictive marker to distinguish Barrett's esophagus patients at risk for malignant transformation. J. Pathol. 208(1), 100-107 (2006).
Brock MV, Gou M, Akiyama Y et al. Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin. Cancer Res. 9(8), 2912-2919 (2003).
Sato F, Jin Z, Schulmann K, Wang J, Greenwald BD, Ito T. Three-tiered risk stratification model to predict progression in Barrett's esophagus using epigenetic and clinical features. PloS ONE 3(4), E1890 (2008).
••Described predictive potential at 2 and 4 years after histological diagnosis based on epigenetic alterations and clinical parameters.
Sato F, Meltzer SJ. CpG hypermethylation in progression of esophageal and gastric cancer. Cancer 106(3), 483-493 (2005).
Kawakami K, Brabender J, Lord RV et al. Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J. Natl Can. Inst. 92(22), 1805-1811 (2000).
Eads CA, Lord RV, Wickramasinghe K et al. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res. 61(8), 3410-3418 (2001).
Ohki R, Nemoto J, Murasawa H et al. Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase. J. Biol. Chem. 275(30), 22627-22630 (2000).
Hamilton JP, Sato F, Jin Z et al. Reprimo methylation is a potential biomarker of Barrett's-associated esophageal neoplastic progression. Clin. Cancer Res. 12(22), 6637-6642 (2006).
Tischoff I, Vieth M, Ell C et al. Methylation of Socs-3 in the carcinogenesis of Barrett's adenocarcinoma. Gut 56(8), 1047-1053 (2007).
Kuester D, Dar AA, Moskaluk CHC 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 9(3), 236-245 (2007).
Bongiorno PF, al-Kasspooles M, Lee SW et al. E-cadherin expression in primary and metastatic thoracic neoplasms and in Barrett's oesophagus. Br. J. Cancer 71(1), 166-172 (1995).
Endo K, Ashida K, Miyake N, Terada T. E-cadherin gene mutations in human intrahepatic cholangiocarcinoma. J. Pathol. 193(3), 310-317 (2001).
Battle E, Sancho E, Franci C et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nat. Cell Biol. 2(2), 84-89 (2000).
Cano A, Perez-Morno MA, Rodrigo I et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2(2), 76-83 (2000).
Jethwa P, Naqvi M, Hardy RG et al. Overexpression of slug is associated with malignant progression of esophageal adenocarcinoma. World J. Gastroenterol. 14(7), 1044-1052 (2008).
Gerson SL, Trey JE, Miller K, Berger NA. Comparison of O6-alkylguanine-DNA alkyltransferase activity based on cellular DNA content in human, rat and mouse tissue. Carcinogenesis 7(5), 745-749 (1986).
Baumann S, Keller G, Napieralski R et al. The prognostic impact of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation in esophageal adenocarcinoma. Int. J. Cancer 119(2), 264-268 (2006).
Lee OJ, Schneider-Stock R, McChesney PA et al. Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis. Neoplasia 7(9), 854-861 (2005).
Tham DM, Whitin JC, Kim KK, Zhu SX, Cohen HJ. Expression of extracellular glutathione peroxidase in human and mouse gastrointestinal tract. Am. J. Physiol. 275(6 Pt 1), 1463-1471 (1998).
Yamamoto Y, Takahashi K. Glutathione peroxidase isolated from plasma reduces phospholipid hydroperoxides. Arch. Biochem. Biophys. 305(2), 541-545 (1993).
Peng DF, Razvi M, Chen H et al. DNA hypermethylation regulates the expression of members of the mu-class glutathione-S-transferases and glutathione peroxidases in Barrett's-related adenocarcinomas. Gut DOI: 10.1136/gut.2007.146290 (2008) (Epub ahead of print).
Vieth M, Schneider-Stock R, Röhricht K et al. INK4a-ARF alterations in Barrett's epithelium, intraepithelial neoplasia and Barrett's adenocarcinoma. Virchows Arch. 445(2), 135-141 (2004).
Jin Z, Hamilton JP, Yang J et al. Hypermethylation of the AKAP12 promoter is a biomarker of Barrett's-associated esophageal neoplastic progression. Cancer Epidemiol. Biomarkers Prev. 17(1), 111-117 (2008).
Jin Z, Olaru A, Yang J et al. Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer. Clin. Cancer Res. 13(21), 6293-6300 (2007).

Cite this: Barrett's Esophagus: Can Biomarkers Predict Progression to Malignancy? - Medscape - Oct 01, 2008.

Box 1. Phases of Biomarker Development for Early Detection of Cancer
Phase 1: preclinical exploratory
• Single laboratory identifies a promising gene; comparison of tumor and normal tissue, selected tissue samples, often at a late stage.
Phase 2: clinical assay and validation
• Phase 1 findings confirmed by other laboratories; reproducibility testing and development of laboratory assays.
Phase 3: retrospective screening
• Wider spectrum of tissue studies (tissue bank); biomarkers evaluated in premalignant disease (assessment of 'lead time'), criteria for a positive screening test defined, limited outcomes.
Phase 4: prospective screening
• Prospective assessment of outcomes; positive predictive tests, feasibility for future controlled trials (Phase 5), ethical issues.
Phase 5: cancer control
• Randomized trial of screening versus 'usual care', assessment of reduced cancer mortality by screening, compliance, acceptability and cost-benefit analysis.

Data from ^[14].

Table 1. Clinical Risk Factors of Esophageal Adenocarcinoma
Variable factor	Increased risk
Age	Older age
Gender	Male
Duration of reflux	>20 years
Obesity	Male-pattern obesity (higher waist:hip ratio)
BMI (kg/m²)	≥30
Hiatus hernia	>4 cm
Barrett segment length	≥6 cm (long segment Barrett's esophagus)
Macroscopic marker	Ulcers, strictures, nodularity
Dysplasia	Especially high-grade dysplasia

Box 2. Molecular Biomarkers That Predict Progression; Evaluated in EDRN Phase 3 and 4 Studies
LOH (9p and 17p) Ploidy (tetraploidy, aneuploidy) Loss of p16 (LOH and promoter methylation) Loss of p53 (LOH and mutation) Cyclin D1 overexpression Short leukocyte telomere length DNA methylation patterns (promoter methylation p16, HPP1 and RUNX3)

EDRN: National Cancer Institute Early Detection Research Network; LOH: Loss of heterozygosity.

Table 2. Molecular Changes and Their Potential Therapeutic Intervention
Cause	Intervention
Inflammation
Acid reflux	PPIs
Free radicals	Antioxidants (e.g., multivitamins, selenium)
Genetic instability
Tetraploidy/aneuploidy	NSAIDs (e.g., aspirin)
Aberrant epigenetic pattern	Demethylating agents, HDAC inhibitors, vitamin B derivates, folic acid
Immortalization
Telomerase overexpression	Telomerase inhibitors
Cell proliferation & growth
EGF and EGFR overexpression	Monoclonal EGFR antibodies Receptor tyrosine kinase inhibitors Inhibitors of EGFR synthesis
MAPK pathway upregulation	MAPK inhibitors (e.g., Resveratrol)
Loss of p16 - methylation	Demethylating agents (e.g., Zebularine, 5´-AZA)
Loss of p16 - LOH	NSAIDs
Loss of Rb	CDK inhibitors (e.g., Flavopiridol)
Loss of APC	Demethylating agents
Apoptosis
COX-2 overexpression	NSAIDs
Fas suppression	Viral gene transfer of Fas ligand
DAPK	Demethylating agents
Angiogenesis
VEGF/VEGFR overexpression	Monoclonal anti-VEGF antibodies
COX-2 overexpression	NSAIDs
Invasion & metastasis
MMP overexpression	MMP inhibitors (e.g., Marimastat)

APC: Adenomatosis polyposis coli; CDK: Cyclin-dependent kinase; DAPK: Death-associated protein kinase; EGF/EGFR: Epidermal growth factor/receptor; HDAC: Histone deacetylase; LOH: Loss of heterozygosity; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; PPI: Proton pump inhibitor; Rb: Retinoblastoma gene.
Modified from ^[58].

Table 3. Methylation in Progression From Barrett's Esophagus to Esophageal Adenocarcinoma
Gene	Location	Function	Barratt's esophagus (%)	Dysplasia (%)	Esophageal adenocarcinoma (%)	Ref.
*p16*	9q21	CDK inhibitor	66-77	47-81	45-85	^[73,74,76]
*p14*	9q21	MDM2 inhibitor	n.d.	n.d.	20	^[95]
*APC*	5q21	β-catenin inhibitor	40-100	89	68-93	^{[74,75,76,78]}
*Reprimo*	2q23.3	Cell cycle	n.d.	64	63	^[81]
*DAPK*	9q34.1	Apoptosis	50	53	20-60	^[76,83]
*E-cadherin*	16q22.1	Cell adhesion	0	10	70	^[76]
*TIMP3*	22q12	MMP inhibitor	60-91	78	56-65	^[76,74,79]
*hMLH1*	3p21.3	Mismatch repair	11	n.d.	9-12	^[76,79]
*MGMT*	10q26	DNA repair	43-60	89	59-73	^[76,79,90]
*GPx3*	5q23	Detoxification	62	82	62-88	^[91,94]
*GPx7*	1p32	Detoxification	20	85	67	^[94]
*GSTM2*	1p13.3	Detoxification	52	61	69	^[94]
*GSTM3*	1p13.3	Detoxification	12	41	15	^[94]
*SOCS-1*	16p13.13	Cytokine inhibitor	0	4-21	42	^[82]
*SOCS-3*	17q25.3	Cytokine inhibitor	13	22-69	74	^[82]
*RUNX3*	1p36	TGFβ signaling	25	n.d.	48	^[76]
*AKAP12*	6q25-q25	Signal transduction	39	52	52	^[96]
*Tachykinin-1*	7q21-q22	Neurotransmitter	56	57	61	^[97]

Table 3. Methylation in Progression From Barrett's Esophagus to Esophageal Adenocarcinoma
Gene	Location	Function	Barratt's esophagus (%)	Dysplasia (%)	Esophageal adenocarcinoma (%)	Ref.
*p16*	9q21	CDK inhibitor	66-77	47-81	45-85	^[73,74,76]
*p14*	9q21	MDM2 inhibitor	n.d.	n.d.	20	^[95]
*APC*	5q21	β-catenin inhibitor	40-100	89	68-93	^{[74,75,76,78]}
*Reprimo*	2q23.3	Cell cycle	n.d.	64	63	^[81]
*DAPK*	9q34.1	Apoptosis	50	53	20-60	^[76,83]
*E-cadherin*	16q22.1	Cell adhesion	0	10	70	^[76]
*TIMP3*	22q12	MMP inhibitor	60-91	78	56-65	^[76,74,79]
*hMLH1*	3p21.3	Mismatch repair	11	n.d.	9-12	^[76,79]
*MGMT*	10q26	DNA repair	43-60	89	59-73	^[76,79,90]
*GPx3*	5q23	Detoxification	62	82	62-88	^[91,94]
*GPx7*	1p32	Detoxification	20	85	67	^[94]
*GSTM2*	1p13.3	Detoxification	52	61	69	^[94]
*GSTM3*	1p13.3	Detoxification	12	41	15	^[94]
*SOCS-1*	16p13.13	Cytokine inhibitor	0	4-21	42	^[82]
*SOCS-3*	17q25.3	Cytokine inhibitor	13	22-69	74	^[82]
*RUNX3*	1p36	TGFβ signaling	25	n.d.	48	^[76]
*AKAP12*	6q25-q25	Signal transduction	39	52	52	^[96]
*Tachykinin-1*	7q21-q22	Neurotransmitter	56	57	61	^[97]

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Barrett's Esophagus: Can Biomarkers Predict Progression to Malignancy?

Five-year View

Clinical Features

Molecular Features

Tables

Tables

Tables

Tables

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Tables

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