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Copyright ©2010 Baishideng Publishing Group Co.
World J Gastroenterol. Dec 7, 2010; 16(45): 5669-5681
Published online Dec 7, 2010. doi: 10.3748/wjg.v16.i45.5669
Table 1 Summary of the most promising biomarkers for identifying patients with Barrett’s esophagus at high risk of developing esophageal adenocarcinoma
Surveillance biomarkerHighest EDRN stageStudy size (n)1FindingsStatistical significanceRef.
HGD415Progression to EA in 4 out of 15 patients with unifocal HGDRR not available[29]
48520 patients with HGD treated with omeprazole only developed EARR not available[30]
32733 out of 76 patients with HGD developed EARR 28 (95% CI: 13-63)[31]
109912 out of 75 patients with HGD developed EARR 12.1 (95% CI: 5-29.4)[32]
Aneuploidy and LOH (Reid Panel)4243Panel of biomarkers (LOH of 17p and 9p and DNA abnormalities) can best predict progression to EARR 38.7 (95% CI: 10.8-138.5)[33]
LOH of 17p aloneRR 10.6 (95% CI: 5.2-21.3)
LOH of 9p aloneRR 2.6 (95% CI: 1.1- 6.0)
Aneuploidy aloneRR 8.5 (95% CI: 4.3-17.0)
Tetraploidy aloneRR 8.8 (95% CI: 4.3-17.7)
p53 positivity by immunohistochemistry3164Diffuse or intense TP53 staining elevated in patients who developed EA compared to controlsOR 11.7 (95% CI: 1.93-71.4)[34]
483 out of 5 patients with low grade dysplasia who progressed to high grade dysplasia had positive p53RR not available[35]
Mcm2327Ectopic luminal surface expression predictive of progression to HGD or EAOR 136 (95% CI: 7.5-2464)[36]
Cyclin A348Ectopic luminal surface expression predictive of progression to HGD or EAOR 7.6 (95% CI: 1.6-37)[37]
Methylation markers353Hypermethylation of p16 (cyclin-dependent kinase inhibitor 2A), RUNX3 (Runt-related transcription factor 3) and HPP1 (transmembrane protein with EGF-like and two follistatin-like domain 2) associated with an increased risk of progression to high grade dysplasia or EAOR 1.74 (95% CI: 1.33-2.2), 1.80 (95% CI: 1.08-2.81) and 1.77 (95% CI: 1.06-2.81), respectively[38]
195A 8 gene methylation panel in combination with age could predict half of progressors to HGD or EA who would not have been diagnosed without the use of the panelRR not available[39]
Table 2 Summary of the biomarkers and the prognostic impact in esophageal adenocarcinoma
Category of cell alterationBiomarkerSample size (n)EndpointFindingsStatistical significanceRef.
Self sufficiency in growth signalsCyclin D124Survival2 of 3 genotypes confers a poorer overall survivalP = 0.0003[77]
EGFR103SurvivalExpression showed a trend towards a correlation with poorer overall survivalP = 0.07[78]
75SurvivalDecreased expression correlated with poorer survival on univariate analysis onlyP = 0.034[79]
Ki-6759SurvivalLow levels (< 10%) of staining correlated with poorer survivalHR: 3.9, P = 0.02[80]
Her2/neu63SurvivalAmplification detected by FISH correlated with poorer survivalP = 0.03[81,82]
TGF-α61SurvivalLow levels significantly correlated with cancer specific deathP = 0.03[83]
87Tumor progression, lymph node metastasisHigh levels significantly correlated with:[84]
Tumor progressionP = 0.025
Lymph node metastasisP < 0.05
Insensitivity to growth inhibitory (antigrowth) signalsTGF-β1123SurvivalOverexpression correlated with poorer survival on univariate analysis onlyP = 0.0255[85]
57SurvivalHigh plasma levels correlated with poorer overall survivalP = 0.0317[86]
APC52SurvivalHigh plasma levels of methylation of APC associated with poorer survivalP = 0.016[87]
P2130SurvivalAlteration in expression after chemotherapy correlated with better survivalP = 0.011[88,89]
Evasion of programmed cell death (apoptosis)P5330SurvivalAlteration in expression after chemotherapy correlated with better survivalP = 0.011[88]
Bcl-235SurvivalExpression correlated with poorer survivalP = 0.03[90]
COX-2100T-stage, N-stage, tumor recurrence and survivalHigher levels expression correlated with:[91]
Higher T-stage,P = 0.008
Higher N-stage,P = 0.049
Increased risk of tumor recurrenceP = 0.01
Poor survivalP < 0.001
20SurvivalStrong staining correlated with poorer survivalP = 0.03[92]
145Distant metastasis, local recurrence and survivalStrong staining correlated with:[93]
Distant metastasisP = 0.02
Local recurrenceP = 0.05
Poorer survivalP = 0.002
NF-κB43SurvivalActivated NF-κB predictive of:[94]
Poorer disease free survivalP = 0.010
Poorer overall survivalP = 0.015
Limitless replicative potentialTelomerase46SurvivalHigher telomere-length ratio shown to be an independent poor prognostic factorP < 0.02[95]
Sustained angiogenesisCD10575Survival, angiolymphatic invasion, lymph node metastasis and tumor stage and distant metastasisSignificant correlation between expression and:[96]
Poorer survivalP < 0.01
Presence of angiolymphatic invasionP < 0.05
More lymph node metastasisP < 0.01
Higher tumor stageP < 0.001
More distant metastasisP < 0.01
VEGF75Survival, angiolymphatic invasion, lymph node metastasis, stage of tumor and distant metastasisSignificant correlation between high expression and:[96]
Poorer survivalP < 0.01
Presence of angiolymphatic invasionP < 0.05
More lymph node metastasisP < 0.01
Higher stage of tumorP < 0.01
More distant metastasisP < 0.01
Tissue invasion and metastasisCadherin59SurvivalReduced level correlated with poorer overall survivalHR: 3.3, P = 0.05[80]
uPA54SurvivalHigh uPA correlated with poorer survivalP = 0.0002[97]
TIMP24Survival and disease stageReduction of expression correlated with poorer overall survival and higher disease stageP = 0.007[98]
P = 0.046
OthersPromoter hypermethylation41Survival and tumor recurrenceEarlier tumor recurrence and poorer overall survival if > 50% of gene profile methylatedP = 0.05[99]
P = 0.04
84DifferentiationHypermethylation of MGMT (Methylated-DNA-protein-cysteine methyltransferase) gene correlated with:P = 0.0079[100]
Higher tumor differentiation
Table 3 Summary of the molecular signatures discovered by microarray technology and latest methods used to correlate molecular alterations and prognosis in patients with esophageal adenocarcinoma
MethodSample size (n)OutcomeFindingsStatistical significanceExternal validationRef.
Oligonucleotide cRNA microarray75SurvivalA 4-gene signature prognosticated patientsP = 0.0001Yes[113]
77Lymphatic spreadCreated a gene signature predicting lymph node metastasisArgininosuccinate synthetase expression (ASS) (P = 0.048)No[114]
19Chemotherapy responseUnsupervised hierarchical clustering divided patients into 2 groups, one of which responded to preoperative chemotherapyNot statistically significantNo[115,116]
47Chemotherapy response86 genes dysregulatedP < 0.001No[117]
Ephrin B3 expression associated with chemotherapy response, tumor grading and stage
Oligonucleotide cDNA microarray46Chemotherapy responseGene signature not predictive in adenocarcinoma of esophagusNot statistically significantNo[118]
Proteomic analysis34Chemotherapy responseHSP27 expression associated with response to chemotherapyP < 0.05No[119]
Single nucleotide polymorphism210Survival and recurrence5 polymorphisms in 3 genes associated with longer recurrence free survival and reduced recurrenceP = 0.004No[120]
microRNAs analysis96SurvivalLow miR-375 levels associated with worse survivalP = 0.002No[121]
Multiplex ligation-dependent probe amplification33SurvivalPatients with more than 12 chromosomal aberrations had a poorer outcome than patients with < 12P = 0.014No[122]