Table 1.
Published evidence from selected studies investigating genetic and epigenetic changes implicated in the metaplasia-dysplasia-carcinoma sequence of Barrett’s esophagus
| Factor | Summary of major findings/conclusions | Ref. |
| Growth self-sufficiency | ||
| Cyclin D1 | ↑ nuclear cyclin D1 immunostaining in 46% BE specimens: -?cyclin D1 overexpression early event in MDC sequence | Arber et al[9] |
| ↑ nuclear cyclin D1 immunostaining in 64% EAC specimens | Arber et al[13] | |
| Cyclin D1 expression correlates with degree of dysplasia in BE | Coppola et al[14] | |
| Cyclin D1 expression 43% BE mucosa (vs 0% normal mucosa) | Umansky et al[15] | |
| Polyphenon E inhibits growth of BE and EAC cells via downregulation of cyclin D1 expression | Song et al[16] | |
| Cyclin E | ↑ cyclin E expression in neoplastic cells in BE | Coppola et al[14] |
| Cyclin E expression 37% BE mucosa (vs 0% normal mucosa) | Umansky et al[15] | |
| p27Kip-1 | 83% EAC specimens displayed low p27 protein levels (despite high p27 mRNA): -p27 inactivated in most BE-associated EAC (post-transcriptional modification)→loss of cell cycle inhibition | Singh et al[17] |
| Experimentally-induced BE and EAC development in mouse model significantly enhanced by p27 gene knockout | Ellis et al[18] | |
| EGF (and EGF-R) | ↑ EGF in cytoplasm of BE epithelial cells (vs gastric mucosa) | Jankowski et al[19] |
| EGF-R expression area in inflamed mucosa (43.1%) significantly > normal mucosa (29.5%); all BE showed positive EGF-R staining | Jankowski et al[20] | |
| EGF/EGF-R expression significantly ↑ in BE and EAC mucosa (vs normal mucosa) by flow cytometry (P < 0.01) | Jankowski et al[21] | |
| EGF-R expression positive in 64% of BE-associated EAC; ↑ staining associated with poorer survival (P = 0.004) | Yacoub et al[22] | |
| EGF A61G G/G genotype associated with >double EAC risk in BE pts (vs A/A or A/G) (OR 2.2) | Lanuti et al[23] | |
| TGF-α | ↑ TGF-α expression in cells from BE and EAC mucosa (vs normal gastric mucosa) by flow cytometry (P < 0.01) | Jankowski et al[21] |
| TGF-α expression positive in 100% of BE-associated EAC | Yacoub et al[22] | |
| HGF (and HGF-R) | HGF expression significantly ↑ in BE specimens (vs normal esophageal mucosa) | Konturek et al[24] |
| Intense HGF-R immunostaining in 100% EAC and dysplastic BE specimens (vs minimal staining in non-dysplastic BE or normal mucosa); HGF-R mRNA and protein levels ↑ in EAC cell lines | Herrera et al[25] | |
| Erb family tyrosine kinases | Membranous c-erbB2 overexpressed in 26% EAC (vs 0% BE with dysplasia): -?later event in MDC sequence | Hardwick et al[26] |
| c-erbB-2 gene amplification in 14% EAC vs 11% HG-dysplasia vs 0% metaplasia/LG-dysplasia specimens | Geddert et al[27] | |
| FGF | Immunostaining intensity for FGF sequentially ↑ from metaplasia/LG-dysplasia (negligible)→HG-dysplasia (weak/moderate)→EAC (moderate/strong) | Soslow et al[28] |
| FGF-1 mRNA and protein expression sequentially ↑ in HG-dysplasia/EAC (vs metaplasia/LG-dysplasia/controls) | Soslow et al[29] | |
| Src family tyrosine kinases | Src-specific activity 3-4-fold ↑ in BE and 6-fold ↑ in EAC (vs controls): -?Src activation early event in MDC sequence | Kumble et al[30] |
| Strong Src expression in 85% EAC vs 93% BE HG-dysplasia vs 72% BE LG-dysplasia vs 27% BE specimens | Iravani et al[31] | |
| Insensitivity to anti-growth signals | ||
| p16 | 9p21 (p16) LOH observed in 89% EAC specimens (vs 0% non-dysplastic BE); homozygous p16 deletion in only 25% | González et al[32] |
| p16 promoter hypermethylation (inactivation) in 75% BE with HG-dysplasia vs 56% LG-dysplasia (vs 3% non-dysplastic BE) | Klump et al[8] | |
| APC | 5q (APC) LOH seen in 80% EAC specimens (and surrounding mucosa) | Barrett et al[33] |
| APC gene LOH observed in 60% EAC specimens (vs 0% non-dysplastic BE) | González et al[32] | |
| APC promoter hypermethylation in 92% EAC vs 40% BE (vs 0% normal esophageal tissues) | Kawakami et al[34] | |
| Avoidance of apoptosis | ||
| p53 | Positive p53 immunostaining in 87% EAC vs 55% BE with HG-dysplasia vs 9% LG-dysplasia vs 0% non-dysplastic BE | Younes et al[35] |
| 17p (p53) LOH found in 91% BE pts who developed aneuploid cell populations: -17p allelic losses precede aneuploidy | Blount et al[36] | |
| p53 overexpression in 64% EAC vs 31% dysplastic BE vs 0% non-dysplastic BE; trend of ↑ p53 expression with ↑tumour grade: -?p53 mutation early event in malignant progression | Symmans et al[37] | |
| p53 immunoreactivity only in EAC/BE with HG-dysplasia (not in BE with LG-/no dysplasia); mutated p53 in 69%: -?late event in MDC sequence (during transition to HG-dysplasia) | Rice et al[38] | |
| p53 protein expression in 85% EAC specimens vs 60% BE with HG-dysplasia vs 7% LG-dysplasia (P < 0.001) | Rioux-Leclercq et al[39] | |
| p53 mutations identified in 75% EAC specimens; p53 overexpression in 58% EAC vs 60% BE with HG-dysplasia vs 12% LG-dysplasia vs 0% non-dysplastic BE | Chung et al[40] | |
| Fas (CD95) | ↓ surface expression of Fas observed in EAC specimens; impaired translocation of Fas to membrane wild-type Fas protein retained in cytoplasm in EAC cell line: -?potential mechanism by which EAC cells evade Fas-mediated apoptosis | Hughes et al[41] |
| ↓ surface expression of Fas and resistance to Fas-mediated apoptosis observed in EAC cell lines | Mahidhara et al[42] | |
| Bcl-xl/Bax/Bcl-2 | Bcl-xl positive in all dysplasia and EAC cells, but negative in 47% non-dysplastic BE: -?switch to anti-apoptotic phenotype in transformation from metaplasia to EAC | van der Woude et al[43] |
| Bcl-2 expression in 84% LG-dysplasia vs 0% HG-dysplasia or EAC | Rioux-Leclercq et al[39] | |
| Cytoplasmic Bcl-xl immunostaining in 59% EAC vs 71% BE/HG-dysplasia vs 60% LG-dysplasia vs 27% non-dysplastic | Iravani et al[31] | |
| COX-2 | ↑ COX-2 mRNA levels in 80% BE and 100% EAC specimens (vs normal gastric controls) (P < 0.001); COX-2 immunostaining strongly positive in 100% BE samples (> gastric controls) | Wilson et al[44] |
| COX-2 immunopositivity in 91% non-dysplastic BE vs 94% dysplastic vs 97% EAC | Lagorce et al[45] | |
| Natural/synthetic COX-2 inhibitors suppressed proliferation, induced apoptosis and blocked cell cycle in EAC cell lines | Cheong et al[46] | |
| Cox-2 mRNA strongly upregulated in experimentally-induced BE epithelium in rat model (vs absent in control animals); COX-2 overexpression observed in human BE patients with dysplasia | Majka et al[47] | |
| Limitless replicative potential | ||
| Telomerase | Telomerase RNA positive in 100% EAC/BE with HG-dysplasia vs 90% LG-dysplasia vs 70% non-dysplastic BE: marked ↑ telomerase RNA accompanies transition along MDC sequence | Morales et al[48] |
| human telomerase reverse transcriptase (catalytic subunit of telomerase) expression ↑ at all stages of BE vs normal controls, and in EAC (P = 0.003) and dysplastic BE (P = 0.056) vs non-dysplastic BE | Lord et al[49] | |
| Telomerase activity (by telomeric repeat amplification protocol assay) ↑ in EAC samples vs adjacent mucosa (P = 0.0002) and in EAC vs BE (P = 0.001); no difference BE vs adjacent mucosa | Barclay et al[50] | |
| Telomerase inhibition (by small interference RNAs) induced senescence in 40% and apoptosis in 86% in BE cell lines | Shammas et al[51] | |
| Sustained angiogenesis | ||
| VEGF (and VEGF-R) | VEGF expression correlated with higher vascularisation in BE and EAC specimens | Couvelard et al[52] |
| VEGF-A expressed in BE epithelium; VEGFR-2 strongly expressed in immature endothelial cells feeding BE epithelium; ↑ VEGF-C expression in BE (vs absent in normal epithelium); ↑ VEGFR-3 in EAC: ?aberrant neovasculature early in MDC sequence | Auvinen et al[53] | |
| VEGF expressed in 64% EAC specimens; significantly correlated with angiolymphatic invasion/survival | Saad et al[54] | |
| VEGF expression significantly ↑ in EAC (> dysplastic BE > BE > normal epithelium) | Griffiths et al[55] | |
| Invasive/metastatic potential | ||
| CAMs | ↓ expression in EAC specimens of E-cadherin (in 74%), α-catenin (60%) and β-catenin (72%) | Krishnadath et al[56] |
| Abnormal expression of β-catenin (P = 0.022), α-catenin (P < 0.01) and E-cadherin (P = 0.049) significantly associated with higher degrees of BE-related dysplasia | Washington et al[57] | |
| ↓ expression of E-cadherin with progression along MDC sequence (P < 0.01); in contrast P-cadherin absent from BE (± dysplasia) but expressed in 67% EAC specimens | Bailey et al[58] | |
| Slug (E-cadherin repressor) immunostaining and mRNA levels overexpressed in EAC vs BE metaplasia specimens: -?Slug upregulation represents mechanism of E-cadherin silencing | Jethwa et al[59] | |
| Cathepsins | Detected amplicon at chromosome 8p22-23 resulting in cathepsin B overexpression (observed in 73% EAC samples) | Hughes et al[60] |
| ↑ cathepsin C expression in EAC (vs BE vs normal) in rat model | Cheng et al[61] | |
| CD44 | Stepwise ↑ cathepsin D mRNA levels in GERD→BE→EAC tissue | Breton et al[62] |
| CD44-H and -V6 variant frequently expressed in BE; differing expression patterns along spectrum normal→dysplastic BE→EAC: -?CD44H and V6 involved in carcinogenesis of BE mucosa | Lagorce-Pages et al[63] | |
| ↓ CD44 expression in EAC/HG-dysplasia (vs BE/LG-dysplasia) | Darlavoix et al[64] | |
BE: Barrett’s esophagus; MDC: Metaplasia-dysplasia-carcinoma; EAC: Esophageal adenocarcinoma; EGF: Epidermal growth factor; EGF-R: EGF receptor; pts: Patients; OR: Odds ratio; TGF: Transforming growth factor; HGF: Hepatocyte growth factor; HGF-R: HGF receptor; mRNA: Messenger RNA; FGF: Fibroblast growth factor; HG: High grade; LG: Low grade; LOH: Loss of heterozygosity; APC: Adenomatous polyposis coli; COX-2: Cyclooxygenase-2; VEGF: Vascular endothelial growth factor; VEGF-R: VEGF receptor; CAM: Cell adhesion molecule; GERD: Gastro-esophageal reflux disease.