Table 3.

Summary of gene expression profiling studies for BE/EAC

Sample sizeArray descriptionOutcomeFindingsExternal validationRef.
BE-21 (paired normal esophageal and gastric samples as control)Serial analysis of gene expression, PCR and immunoblottingDisease progressionOf note, 534 tags were significantly differentially expressed between normal esophageal squamous epithelium and Barrett's esophagus. The most upregulated genes in Barrett's esophagus as compared with normal epithelium were identified to be trefoil factors, annexin A10 and galectin-4 with each different type of tissue showed an unique cytokeratin expression.No(181)
Barrett's esophagus and HGD-11 (matched biopsy samples)cDNA microarrayDisease progressionUsing 2.5-fold cutoff, identified 131 upregulated and 16 downregulated genes in HGD. Twenty-four of 28 most significantly different genes showed similar changes during validation.Real-time PCR(182)
EAC-91Oligo-microarrayDisease progressionA 4-gene panel consists of deoxycytidine kinase, 3′-phosphoadenosine 5′-phosphosulfate synthase 2, sirtuin-2, and tripartite motif-containing 44 predicted 5-year survival.Immunohistochemistry(183)
Twenty-three paired Barrett's esophagus and normal epithelium samplesTranscriptional profiling and proteomicsDisease progressionIdentified 2,822 genes to be differentially expressed between Barrett's esophagus and normal epithelium. Significantly overexpressed genes during Barrett's esophagus belonged to cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production and bioenergetics. While genes encoding HSP and various kinases were downregulated.No(184)
Lymph node metastatic (n = 55) and nonmetastatic (n = 22) EAC samplesOligo-microarrayDisease progressionLymph node–positive samples showed significant downregulation of argininosuccinate synthetase as compared with lymph node nonmetastatic samples (P = 0.048).No(185)
EAC-6 and gastric cardia cancer-8aCGHDisease progressionIdentified HGF (45%) and BCAS1 (27%) to be most frequently overexpressed genes respectively at 7q21 and 20q13 locus.No(186)
Eleven matched sample sets (healthy-BE-EAC matched-6, normal-BE matched-4 and normal-EAC matched-1)SNP microarrayDisease progression60% of Barrett's esophagus and 57% of EAC samples contained at least one of the genomic alterations in the form of deletions, duplications, amplifications, copy number changes, and neutral LOH.No(187)
Normal-39, BE-25, EAC-38, and ESCC-26cDNA microarrayDisease progressionClustering showed the separation of samples into 4 distinct groups. Of note, 2,158 clones were differentially expressed between normal and Barrett's esophagus samples, whereas 1,306 between Barrett's esophagus and EAC. BE/EAC samples showed differential expression of hydrolases, lysozyme, fucosidase, transcription factors, mucins, and the trefoil factors.No(188)
BE-20, LGD-19, HGD-20 and EAC-42SNP microarrayDisease progressionIncreasing numbers of SNPs and loss of chromosomes with disease progression. Chromosomal disruption was identified in the FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2 genes in EAC.No(189)
EAC-75 specimens from 64 patients, adjacent paired normal tissue from patients with EAC-28DNA microarrayDisease progressionIdentified AKR1B10, CD93, CSPG2, DKK3, LUM, MMP1, SOX21, SPP1, SPARC, and TWIST1genes as biomarker based on transcriptomics data. Quantitative real-time PCR identified SPARC and SPP1 genes to be associated with EAC patient survival (P < 0.024).Real-time PCR(190)
EAC-8, gastric cardia cancer-3aCGH and cDNA microarrayDisease progressionTranscriptomics data identified 11 genes to be differentially expressed (ELF3, SLC45A3, CLDN12, CDK6, SMURF1, ARPC1B, ZKSCAN1, MCM7, COPS6, FDFT1, and CTSB). IHC analysis revealed significant overexpression of CDK6 a cell-cycle regulator in tumor samples.No(191)
BE-20aCGH arrays and high density SNP genotypingDisease progressionCopy number losses were detected at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%) sites in early Barrett's esophagus. Validation study confirmed loss of FRA3B and FRA16D in early Barrett's esophagus samples.Real-time PCR and pyrosequencing(192)
BE-11, gastroesophageal junction (GEJ) adenocarcinoma-11aCGH with a whole chromosome 8q contig arrayDisease progressionOverexpression of MYC and EXT1, while downregulation of MTSS1, FAM84B, and C8orf17 is significantly associated with GEJ adenocarcinoma.(193)
BE-14, EAC-5, ESCC-3cDNA microarrayDisease progressionIdentified 160 genes that can differentiate between Barrett's esophagus and esophageal cancer.No(194)
Twenty-four paired samples of normal, Barrett's esophagus, and EAC phenotypecDNA microarrayDisease progressionOf note, 214 differentially regulated genes could differentiate between normal, Barrett's esophagus, and EAC phenotype. Genes involved in epidermal differentiation are underexpressed in EAC as compared with Barrett's esophagus. Expression ratio of GATA6 to SPRR3 can differentiate between 3 phenotypes studied.No(195)
Pooled biospy samples from Barrett's esophagus, esophageal squamous, gastric, and duodenumOligo-microarrayDisease progressionDifferentiate different tissue clusters based on gene expression profile. Identified 38 genes that are upregulated in Barrett's esophagus tissue cluster, which belong to cell cycle (P1cdc47, PCM-1), cell migration (urokinase-type plasminogen receptor, LUCA-1/HYAL1), growth regulation (TGF-β superfamily protein, amphiregulin, Cyr61), stress responses (calcyclin, ATF3, TR3 orphan receptor), epithelial cell surface antigens (epsilon-BP, ESA, integrin β4, mesothelin CAK-1 antigen precursor), and 4 mucins.No(196)
Normal-24, BE-18, EAC-9cDNA microarrayDisease progressionIdentified 457, 295, and 36 differentially expressed genes, respectively, between normal-EAC, normal- Barrett's esophagus, and BE–EAC groups.No(197)
89-EACcDNA-mediated annealing, selection, extension, and ligation assay with 502 known cancer-related genesDisease progressionIdentified differential gene expression between early stages of EAC (T1 and T2) vs. late (T3 and T4). Gene expression profile revealed ERBB4, ETV1, TNFSF6, MPL genes to be common between advanced tumor stage and lymph node metastasis.No(198)
Normal esophageal mucosa-9, esophagitis-6, BE-10, EAC-5, GEJ adenocarcinoma-9, stomach samples-32 (normal mucosa-11, IM-9, intestinal-type adenocarcinoma-7, and diffuse carcinoma-5)cDNA microarrayDisease progressionOn the basis of the expression profile, genes associated with the lipid metabolism and cytokine nodule are found to be significantly altered between EAC and other groups.No(199)
Seventeen paired samples of normal, BE/EACcDNA microarrayDisease progressionEach tissue type expresses distinct set of genes, which can differentiate between their phenotypes. Barrett's esophagus and EAC expresses similar set of stromal genes that are different from normal epithelium.No(200)
BE-19, EAC-20 (98 tissue specimens were collected and categorized into different groups)On the basis of previous microarray studies 23 genes were validated using real-time PCRDisease progressionOut of 23 genes, panel of 3 genes (BFT, TSPAN, and TP) was able to discriminate between Barrett's esophagus and EAC in internal validation with 0% classification error.N.A.(201)
Normal-30, BE-31, gastric mucosa-34, duodenum-18Biomarkers for Barrett's esophagus were identified using 3 publicly available microarray datasets and validated using real-time PCR and immunohistochemistry.Disease progressionOut of 14 genes identified, dopa decarboxylase (DDC) and Trefoil factor 3 (TFF3) were validated to be upregulated in Barrett's esophagus.N.A.(202)
EAC-56Oligonucleotide microarray and aCGHDisease progressionIdentified 4 new genes (EGFR, WT1, NEIL2, and MTMR9) to be overexpressed in 10% to 25% EAC. Expression levels of these 4 genes differentiated patients with EAC into 3 groups namely good, average, and poor depending upon their prognosis (P < 0.008)Immunohistochemistry(203)
BE/LGD-72, HGD-11, EAC-15Bacterial artificial chromosome aCGHDisease progressionCopy number changes were more common and larger as disease progress to later stages. Patients having copy number alterations involving more than 70 Mbp were at increased risk of progression to EAC (P = 0.0047)No(60)
EAC-30, BE-6, LGD-9, HGD-10Genome-wide CGHDisease progressionLoss of 7q33-q35 was found in HGD as compared with precursor LGD (P = 0.01). Loss of 16q21-q22 and gain of 20q11.2-q13.1 was significantly different between HGD and EAC (P = 0.02 and 0.03, respectively).No(56)
EAC-30, lymph node metastasis-8, HGD-11, LGD-8, and BE-6 from 30 EAC patient biopsy samplesCGHDisease progressionIdentified regions undergoing copy number loss and amplification during each stage of transition. Average number of chromosomal imbalance sequentially increased from BE–LGD–HGD–EAC–lymph node metastasis.No(54)
Forty-two patients represent different stages of diseaseSNP arrayDisease progressionSNP abnormalities increases from 2% to more than 30% as the disease progress from Barrett's esophagus to EAC. Total number of SNP alterations in tissue samples is tightly correlated with DNA abnormalities such as aneuploidy and LOH.No(57)
EAC-27 and matched normal-14SNP arrayDisease progressionConfirmed previously described genomic alterations such as amplification on 8q and 20q13 or deletion/LOH on 3p and 9p. Also identified alterations in several novel genes and DNA regions in EAC samples.No(58)
EAC-26SNP arrayDisease progressionConfirmed previously reported frequent changes to FHIT, CDKN2A, TP53, and MYC genes in EAC. Identified PDE4D and MGC48628 as tumor-suppressor genes.No(59)
EAC-35cDNA microarrayResponse to chemotherapyIdentified 165 differentially expressed genes between poor (n = 17) and good outcome (n = 18) patient groups. Top functional pathway based on differential gene expression was identified to be Toll-receptor signaling.No(204)
EAC-47 (locally advanced tumor)cDNA microarrayResponse to chemotherapyIdentified 86 genes showing at least 2-fold difference between chemotherapy responders (n = 28) and nonresponders (n = 19). Ephrin B3 receptor, which showed highest difference between the groups, showed strong membrane staining in chemotherapy responding tumors using immunohistochemistry.No(205)
Patients with EAC-19 undergoing chemoradiotherapyOligo-microarrayResponse to chemoradiotherapyReduced expression of IVL, CRNN, NICE-1, S100A2, and SPPR3 genes correlated with poor survival and nonresponse to chemotherapy.No(206)
19 patients (EAC-16, ESCC-2 and adenosquamous carcinoma-1) undergoing chemoradiotherapyOligo-microarrayResponse to chemoradiotherapyLower expression for panel of genes PERP, S100A2, and SPRR3 was associated with nonresponse to therapy. Pathway analysis identified downregulation of apoptosis in nonresponders.No(207)
EAC-174, ESCC-36SNPs associated with the chemotherapy drug action pathwayResponse to chemoradiotherapyIdentified association between genetic polymorphisms and response to preoperative chemotherapy (fluorouracil and platinum compounds) and radiotherapy.No(208)

NOTE: Majority of studies described in this table include validation of results in the same patient cohort as used in discovery phase. Only studies that included validation using independent patient cohort are described as external validation.