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

Iris Tischoff; Andrea Tannapfel

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

Molecular Profiling

In the last 20 years, quantitative and comprehensive molecular profiling methods, such as cDNA microarrays, proteomics or serial analysis of gene expression (SAGE), have been developed. This has enabled the detection of alterations of multiple genes in one tissue sample, the construction of expression profiles of tumors and the screening for new candidate molecular biomarkers. In Barrett's lesions, newly identified genes are involved in development, differentiation and tumorigenesis, such as members of zinc-finger proteins that are inactivated in hepatocellular carcinoma and colorectal carcinoma (Klf6), or overexpressed in pancreatic carcinoma (Znf146); other genes include LG11 or Dr5. Dr5 is one of the cell death-inducing receptors for TNF-related apoptosis-inducing ligands and is upregulated in EA. However, further studies are needed to prove its role in the pathogenesis of BE.^[69,70,71]

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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?

Molecular Profiling

Molecular Profiling

Tables

Tables

Tables

Tables

Tables

Tables

Authors and Disclosures

Authors and Disclosures

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