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Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma

Written2009-08DunFa Peng, Wael El-Rifai
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

(Note : for Links provided by Atlas : click)


ICD-Topo C150-C155,C158-C159 ESOPHAGUS
Atlas_Id 5591
Phylum Digestive organs:Esophagus::Barretts esophagus
WHO/OMS Classification Digestive organs
Note Barrett's adenocarcinoma is one of malignancies with the most rapid increase in incidence during past decades in the Western countries. It is defined as adenocarcinoma of the lower esophagus and gastroesophageal junction associated with Barrett's esophagus. Barrett's esophagus is the only known precursor for Barrett's adenocarcinoma through Barrett's dysplasia (also called metaplasia-dysplasia-adenocarcinoma sequence).

Clinics and Pathology

Disease Barrett's Esophagus
Note Barrett's esophagus is defined as the normal esophageal squamous epithelium that is replaced by intestinalized metaplastic columnar epithelia.
Phenotype / cell stem origin The progenitor cell from which Barrett's oesophagus develops is still unclear. Progenitor cells resident in the submucosal glands or the interbasal layer of the epithelium, bone-marrow-derived stem cells, or transdifferentiated squamous cells are included in the candidate cells.
Etiology Gastroesophageal reflux disease (GERD) is considered the major risk factor for Barrett's esophagus. About 1 in 10 patients with GERD are found to have Barrett's esophagus. GERD generates reactive oxygen species that produce oxidative stress and subsequent oxidative DNA damage. Some DNA damage may cause DNA mutations that accumulate and cause tumor formation.
Epidemiology Barrett's esophagus is more common in men than in women, with a male:female ratio of about 2:1. The risk factors of Barrett's esophagus include Age (increasing with age), Race (more common in Caucasians), smoking (not clear), alcohol consumption (not clear), gastroesophageal reflux disease (GERD, major factor), and obesity. On the other hand, some controversial reports indicate that H. pylori infection and the virulent cagA strains in particular, may protect against the development of Barrett's oesophagus and progression to adenocarcinoma.
Clinics Heartburn is the most common symptom of GERD and Barrett's esophagus.
Normal esophagus is covered by squamous epithelia (A). However, in Barrett's esophagus (B), the squamous epithelia are replaced by intestinalized metaplastic columnar epithelia.

Disease Barrett's dysplasia
Note Barrett's dysplasia is defined morphologically as unequivocal neoplastic epithelium that remains confined within the basement membrane of the epithelium from which it developed. In patients with Barrett's esophagus, dysplasia is graded as either low or high, depending on its cytological and architectural features.
Epidemiology Most Barrett's esophagus never progress to dysplasia and carcinoma. It has been reported that the male gender, longstanding gastroesophageal reflux disease, hiatal hernia size, and segment length are strongly associated with Barrett's dysplasia. On the other hand, successful antireflux surgery protects the Barrett's mucosa from developing high-grade dysplasia and esophageal adenocarcinoma.

Disease Barrett's adenocarcinoma
Note Adenocarcinoma of lower esophagus and gastroesophageal junction associated with Barrett's esophagus through metaplasia-dysplasia-adenocarcinoma sequence.
Classification: Tumor classification is based on UICC TNM classification for esophageal cancers.
Etiology Barrett's esophagus with dysplasia
Epidemiology Barrett's esophagus is the only known precursor for Barrett's adenocarcinoma. The patients with Barrett's esophagus have 20 folds more risk for developing esophageal adenocarcinoma. However, only 1-5% of Barrett's esophagus progress to Barrett's adenocarcinoma. Although longstanding gastroesophageal reflux disease, hiatal hernia size, and segment length are strongly associated with adenocarcinoma, Barrett's esophagus with dysplasia is likely the true precursor for developing to adenocarcinoma.
Clinics Heartburn is the most common symptom of GERD and Barrett's esophagus. As for Barrett's adenocarcinoma, it shares the symptoms with other esophageal type cancers, such as difficulty swallowing, unexplained weight loss, pain in the throat or mid-chest, etc.
Pathology There is no difference in the term of histology of Barrett's adenocarcinoma from that in the stomach and colon. It can be graded into well-, moderately- and poorly-differentiated adenocarcinoma based on their cytologic and architectural atypia. The Lauren classification for gastric cancer has also been used by some pathologists and physicians to divide into either intestinal or diffuse histological type.
A representative image of a Barrett's adenocarcinoma with moderate to poor differentiation. Atypic tumor cells form quite irregular tubules and some form solid cord.
Treatment Esophagectomy is still the most common primary treatment. Other treatment modalities include chemotherapy, radiation therapy, stents, photodynamic therapy, and endoscopic therapy with an Nd:YAG laser. Combined modality therapy (i.e., chemotherapy plus surgery or chemotherapy and radiation therapy plus surgery) is under clinical evaluation.
Prognosis The prognosis of Barrett's adenocarcinoma depends on the stage at diagnosis, treatment and the patients' general condition. The overall 5-year survival rate in patients amenable to definitive treatment ranges from 5 to 30%.


Note The chromosomal alterations most frequently identified in Barrett's adenocarcinoma by CGH were: gains in 8q (80%), 20q (60%); 2p, 7p and 10q (47% each), 6p (37%), 15q (33%), and 17q (30%). Losses were observed predominantly in the 4q (50%); 5q and 9p (43% each), 18q (40%), 7q (33%), and 14q (30%).
CGH analysis of a case of Barrett's esophageal adenocarcinoma. Tumor DNA was labeled with FITC (Green) and reference DNA was labeled with TRITC (red). The hybridizations were analyzed using an Olympus fluorescence microscope and the ISIS digital image analysis system (Metasystems GmbH, Altlussheim, Germany) based on integrated high-sensitivity monochrome CCD camera and automated CGH analysis software. The green colon indicates areas of DNA gains whereas the red color indicates DNA losses in the tumor sample.

Genes involved and Proteins

Note There are many genes that have been reported to be genetically and/or epigenetically dysregulated, such as gene mutation, amplification, and LOH and DNA methylation that involved cell cycle control, apoptosis, cell adhesion and antioxidative stress, etc. Some representative genes are described below.
Gene NameERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Location 17q12
Note ERBB2 protein over-expression and/or DNA amplification have been reported in 10-70% of esophageal adenocarcinomas. The present literature data suggest that ERBB2 overexpression may be a late event in the dysplasia-carcinoma sequence, as it occurred predominantly in high-grade dysplasia and adenocarcinomas. It has been reported that ERBB2 over-expression/amplification in carcinoma correlated significantly with tumor invasion, lymph node metastasis, and poor prognosis in patients with Barrett's related adenocarcinoma.
Protein The ERBB2 (also called HER2 or NEU) gene encodes an integral type I protein of 185 kDa, 1255 amino acids, with a cysteine-rich extracellular ligand-binding domain, a transmembrane domain and an intracellular region endowed with a tyrosine kinase activity.

Gene NameMYC v-myc myelocytomatosis viral oncogene homolog (avian)
Location 8q24.21
Note Frequent high-level chromosomal amplification of 8q21 has been reported in Barrett's adenocarcinoma and c-myc is the potential target gene for this amplification. It has been reported that amplification of c-myc was detected in 25% of high-grade dysplasia and 44% of adenocarcinomas, but in none of Barrett's metaplasia and low-grade dysplasia.
Protein DNA binding protein with 439 amino acids and 48 kDa (p64); 454 amino acids (p67, 15 additional amino acids in N-term), contains a transactivation domain, an acidic domain, a nuclear localization signal, a basic domain, a helix-loop-helix motif, and a leucin zipper.

Gene NameCDX1 (caudal type homeobox 1)
Location 5q32
Note CDX1 is predominantly expressed in the small intestine and colon, but not in normal esophageal squamous epithelia or gastric epithelia.
CDX1 was over-expressed in Barrett's esophagus and adenocarcinomas, most likely through promoter DNA hypomethylation.
Protein Member of the caudal-related homeobox transcription factor gene family. The encoded protein regulates intestine-specific gene expression and differentiation of intestine.

Gene NameCDX2 (caudal-related homeobox 2)
Location 13q12.2
Note CDX2 is predominantly expressed in the small intestine and colon, but not in normal esophageal squamous epithelia or gastric epithelia.
CDX2 expression is observed in the intestinal metastasis area.
Protein Member of the caudal-related homeobox transcription factor gene family. The encoded protein regulates intestine-specific gene expression and differentiation of intestine. It is suggested that CDX2 is a master switch gene whose normal expression determines the proximal and distal specialization of the gut in embryogenesis.

Gene NameCDKN2A (cyclin dependent kinase 2a / p16)
Location 9p21.3
Note Tumor suppressor gene controls the G1/S transition of the cell cycle. Inactivation of CDKN2A is among the most common genetic/epigenetic alterations through Barrett's carcinogenesis and is an early event. LOH, promoter hypermethylation, or sequence mutations have been reported in over 85% of Barrett's esophagus that were associated with p16 inactivation.
Dna / Rna 7288 bp.
Exon Count: 3.
Protein Tumor suppressor protein having 156 aa, functions as an inhibitor of CDK4 kinase in cell cycle G1 control.

Gene NameTP53 (Tumour protein p53 (Li-Fraumeni syndrome))
Location 17p13.1
Note Loss of p53 occurs through either LOH, sequence mutation, or both. Loss of p53 has been reported in Barrett's esophagus and likely correlates with progression to adenocarcinoma, as patients with LOH in TP53 are 16 times more likely to progress to adenocarcinoma than patients without TP53 LOH.
Dna / Rna Exon Count: 11.
Protein A tumor suppressor protein essential in cell cycle regulation and in DNA damage repair. p53 transcriptionally regulates multiple genes functioning as an inhibitor of cell growth and proliferation and inducer of apoptosis. Loss of TP53 functions promotes tumor progression, most likely by preventing cell cycle arrest, suppressing apoptosis and permitting genetic instability for subsequent genetic alterations.

Gene NameCDKN1B (cyclin-dependent kinase inhibitor 1 B)
Location 12p13.1
Note It has been reported that in 83% of Barrett's adenocarcinomas, p27 protein was down-regulated by an immunohistochemical study. And for p27 to arrest cell cycle, it must localize in the nucleus. However, in approximately 50% of high-grade dysplasia, p27 was observed in cytoplasmic localization, which renders it inactive.
Protein A tumor suppressor protein essential in cell cycle regulation, a CDK inhibitor.

Gene NameGPX3 (Glutathione peroxidase 3)
Location 5q33.1
Note GPX3 is one of the glutathione peroxidase family members, which functions in the detoxification of hydrogen peroxide. Frequent GPX3 gene promoter hypermethylation has recently been demonstrated in Barrett's adenocarcinomas and its precancerous lesions, Barrett's esophagus and dysplasia, and was significantly associated with gene down-regulation. It is noted that GPX3 has been recently reported as a potential tumor suppressor in prostatic carcinomas.
Protein GPX3 is a secretory protein.

Gene NameGPX7 (glutathione peroxidase 7)
Location 1p32.3
Note GPX7 is one of the glutathione peroxidase family members which function in the detoxification of hydrogen peroxide. Unlike other glutathione peroxidase family members, GPX7 incorporates cysteine instead of selenocysteine in the conserved catalytic motif. Frequent GPX7 gene promoter hypermethylation has recently been demonstrated in Barrett's adenocarcinomas and its precancerous lesion, Barrett's dysplasia, and was significantly associated with gene down-regulation. Recent research indicates that GPX7 may have dual functions, antioxidative activity and tumor suppressor function in Barrett's adenocarcinoma.
Dna / Rna Genomic Size: 6679.
Exon Count: 3.
Coding Exon Count: 3.

Gene NameMGMT (O-6-methylguanine-DNA methyltransferase)
Location 10q26.3
Note It is recently reported that hypermethylation was detected in 78.9% of esophageal adenocarcinomas, in 100% of Barrett's intraepithelial neoplasia, in 88.9% of Barrett's metaplasia, in only 21.4% of normal esophageal mucosa samples (P<0.001), and correlated significantly with the down-regulation of MGMT transcripts (P=0.048) and protein expression (P=0.02). The decrease of protein expression was significantly correlated with progressed stage of disease, lymph node invasion and tumor size.
Dna / Rna Genomic Size: 299903.
Exon Count: 5.
Coding Exon Count: 4.
Protein O6-methylguanine-DNA methyltransferase is involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. It repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O6 position to a cysteine residue in the enzyme.

Gene NameAPC (adenomatous polyposis coli)
Location 5q22.2
Note LOH of 5q has been reported as a higher occurrence in high-grade dysplasia and adenocarcinomas of the esophagus. Hypermethylation of the APC gene has been found in 68-100% of Barrett's adenocarcinomas and approximately 50% of Barrett's esophagus. More importantly, hypermethylation of APC with other genes such as p16, strongly predicts progression to high-grade dysplasia or cancer in patients with BE. Absence of p16 and APC hypermethylation is associated with a benign course.
Dna / Rna Genomic Size: 138719.
Exon Count: 16.
Coding Exon Count: 15.
Protein Adenomatous polyposis coli protein which possesses tumor suppressor functions, works as an antagonist of the Wnt signaling pathway. APC binding to beta catenin leads to ubiquitin-mediated beta catenin destruction; loss of APC function increases transcription of beta catenin targets, such as C-MYC and Cyclin D. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product.


The lower esophagus lined by columnar epithelium.
Barrett NR.
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PMID 13442856
p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus.
Bian YS, Osterheld MC, Fontolliet C, Bosman FT, Benhattar J.
Gastroenterology. 2002 Apr;122(4):1113-21.
PMID 11910361
Genetic differences between adenocarcinomas arising in Barrett's esophagus and gastric mucosa.
El-Rifai W, Frierson HF Jr, Moskaluk CA, Harper JC, Petroni GR, Bissonette EA, Jones DR, Knuutila S, Powell SM.
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PMID 11522743
Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma.
Fitzgerald RC.
Gut. 2006 Dec;55(12):1810-20. (REVIEW)
PMID 17124160
The molecular biology of esophageal adenocarcinoma.
Koppert LB, Wijnhoven BP, van Dekken H, Tilanus HW, Dinjens WN.
J Surg Oncol. 2005 Dec 1;92(3):169-90. (REVIEW)
PMID 16299787
Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus.
Kuester D, El-Rifai W, Peng D, Ruemmele P, Kroeckel I, Peters B, Moskaluk CA, Stolte M, Monkemuller K, Meyer F, Schulz HU, Hartmann A, Roessner A, Schneider-Stock R.
Cancer Lett. 2009 Mar 8;275(1):117-26. Epub 2008 Nov 21.
PMID 19027227
Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis.
Lee OJ, Schneider-Stock R, McChesney PA, Kuester D, Roessner A, Vieth M, Moskaluk CA, El-Rifai W.
Neoplasia. 2005 Sep;7(9):854-61.
PMID 16229808
Multistage carcinogenesis in Barrett's esophagus.
Maley CC.
Cancer Lett. 2007 Jan 8;245(1-2):22-32. Epub 2006 May 19. (REVIEW)
PMID 16713672
Barrett esophagus: risk factors for progression to dysplasia and adenocarcinoma.
Oberg S, Wenner J, Johansson J, Walther B, Willen R.
Ann Surg. 2005 Jul;242(1):49-54.
PMID 15973101
DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett's adenocarcinoma.
Peng DF, Razvi M, Chen H, Washington K, Roessner A, Schneider-Stock R, El-Rifai W.
Gut. 2009 Jan;58(1):5-15. Epub 2008 Jul 29.
PMID 18664505
Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: serial analysis of gene expression.
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PMID 17636545
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This paper should be referenced as such :
Peng, D ; El-Rifai, W
Esophagus: Barrett's esophagus, dysplasia, adenocarcinoma
Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):698-703.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 45 ]


External links

arrayMap Topo ( C15) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Other databaseTumor Portal - Broad Institute
Other databasecBioPortal: Esophageal Adenocarcinoma (Broad, Nature Genetics 2013)
Other databaseEsophageal carcinoma (ESCA) TCGA Copy Number Portal
Other databaseEsophageal carcinoma ( intOGen )
Other databaseEsophageal Carcinoma [ Genomic Data Commons - NCI TCGA-ESCA]
Disease databaseEsophagus: Barrett's esophagus, dysplasia and adenocarcinoma
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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