TP53 and progression from Barrett's metaplasia to oesophageal adenocarcinoma in a UK population cohort

Liam Murray ¹, Alicia Sedo ², Michael Scott ³, Damian McManus ³, James M Sloan ⁴, Laura J Hardie ², David Forman ² and Christopher P Wild ^2*

¹ The Queen's University of Belfast, Northern Ireland
² University of Leeds, United Kingdom
³ Belfast City Hospital Trust, Northern Ireland
⁴ The Royal Hospitals Trust, Northern Ireland

^* To whom correspondence should be addressed. E-mail: c.p.wild{at}leeds.ac.uk.

Accepted 16 March 2006

Abstract

Background and Aims: Oesophaegal adenocarcinoma frequently develops on a background of metaplastic Barrett's epithelium. The development of malignancy is accompanied by genetic alterations, which may be promising biomarkers of disease progression.

Methods: A case control study was conducted nested within a large unselected population-based cohort of Barrett's patients. Incident oesophageal malignancies and high grade dysplasias were identified. For each case upto five controls were matched on age, sex and year of diagnosis. Biopsies from the time of diagnosis of Barrett's epithelium were stained immunohistochemically for TP53, cyclin D1, COX-2 and -catenin proteins.

Results: Twenty-nine incident oesophageal malignancies and six cases of high grade dysplasia were identified. The odds of diffuse or intense TP53 staining were substantially elevated in biopsies from patients who developed oesophageal adenocarcinoma compared to controls; odds ratio (OR) 11.7; 95% CI: 1.93, 71.4. This difference was also present when all cases were considered with an OR 8.42; 95% CI: 2.37, 30.0. Despite the association with TP53 staining, only 32.4% of cases had an initial biopsy showing diffuse/intense TP53 staining. There were no significant associations between cyclin D1, COX-2 or -catenin staining and case:control status. The odd ratio for positive staining for both TP53 and COX-2 was markedly increased in cases compared to controls, OR 27.3; 95% CI: 2.89, 257.0, although only 15% of cases had positive staining for both markers.

Conclusions: Immunohistochemical detection of TP53 expression is a biomarker of malignant progression in Barrett's oesophagus but the sensitivity is too low to act as a criterion to inform endoscopic surveillance strategies. Additional biomarkers are required which when combined with TP53 will identify, with adequate sensitivity and specificity, Barrett's patients who are at risk of developing cancer.

Keywords: Barrett's oesophagus, TP53, biomarkers, cyclin D1, oesophageal adenocarcinoma

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