OESOPHAGUS

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

L Murray¹, A Sedo², M Scott³, D McManus³, J M Sloan⁴, L J Hardie², D Forman⁵, C P Wild²

¹ Centre for Clinical and Population Sciences, The Queen’s University of Belfast, Mulhouse Building, The Royal Group of Hospitals, Belfast, UK
² Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute for Genetics Health and Therapeutics, The LIGHT Laboratories, University of Leeds, UK
³ Tissue Pathology, Belfast Link Laboratories, Belfast City Hospital Trust, Belfast, UK
⁴ Tissue Pathology, Belfast Link Laboratories, The Royal Hospitals Trust, Belfast, UK
⁵ Cancer Epidemiology Group, Centre for Epidemiology and Biostatistics, Leeds Institute for Genetics Health and Therapeutics, University of Leeds, UK

Correspondence to:
Professor C P Wild
Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute for Genetics Health and Therapeutics, The LIGHT Laboratories, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK; c.p.wild{at}leeds.ac.uk

Background and aims: Oesophageal 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 up to 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, cyclooxygenase 2 (COX-2), and ß-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 with controls (odds ratio (OR) 11.7 (95% confidence interval (CI) 1.93, 71.4)). This difference was also present when all cases were considered (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 ß-catenin staining and case control status. The OR for positive staining for both TP53 and COX-2 was markedly increased in cases compared with 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 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.

Abbreviations: OA, oesophageal adenocarcinoma; BO, Barrett’s oesophagus; SIM, specialised intestinal metaplasia; LOH, loss of heterozygosity; COX-2, cyclooxygenase 2; H&E, haematoxylin and eosin; NIBR, Northern Ireland Barrett’s Oesophagus Register; TBS, Tris buffered saline; OR, odds ratio

Keywords: Barrett’s oesophagus; cyclin D1; TP53; oesophageal adenocarcinoma; biomarkers

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