Genetic versus environmental interactions in the oesophagitis-metaplasia-dysplasia-adenocarcinoma sequence (MCS) of Barrett's oesophagus.
The prevalence of Barrett's oesophagus has risen over a short time interval implying environmental in addition to genetic aetiological factors. Bile salt effects from duodenogastro-reflux are assuming increasing importance with deoxycholic and taurodeoxycholic acid being particularly associated with Barrett's oesophagus. The cellular biology changes appear to follow a progression from initial inflammation and oesophagitis to metaplasia and dysplasia through to adenocarcinoma. Mechanisms of restitution include epidermal growth factor mediated increases in epithelial thickness. This results in basal stem cells becoming superficially placed and exposed further to luminal refluxed bile salts. Immature stem cells result which undergo mutation to a metaplastic glandular phenotype with intestinal metaplasia. P53 mutation increasingly occurs in progression to dysplasia and carcinoma and may confer a survival advantage of these cell clones by delaying apoptosis. Cell cycling gene mutations occur with accumulation of cells in G2 phase. Disruption of cellular checkpoint mechanisms in the mitotic process result in loss of heterozygosity and aneuploidy including loss of the Y chromosome. Identical mutations between adjacent areas of dysplasia and adenocarcinoma supports clonal expansion as the mechanism of carcinogenesis. APC tumour suppressor gene mutations are conserved in synchronous carcinomas in Barrett's dysplasia and are associated with beta-catenin accumulation in the nucleus and cellular migration with invasion. Cumulative genetic errors result in abnormal clones with metastatic or angiogenic potential. When a clone with malignant potential occurs adenocarcinoma can result completing the progression from inflammation to metaplasia and dysplasia through to adenocarcinoma.
Ransford
R A
RA
Department of Medicine, Queen Elizabeth Hospital, Birmingham, UK.
Jankowski
J A
JA
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D001471:Barrett Esophagus / Q000209:etiology* / Q000473:pathology*; D004781:Environmental Exposure / Q000009:adverse effects; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D004941:Esophagitis / Q000235:genetics / Q000473:pathology*; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications; D006801:Humans; D008297:Male; D018570:Risk Assessment; D012680:Sensitivity and Specificity