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

Abstract

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 b-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 b-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.

Gene expression alterations in formalin-fixed, paraffin-embedded Barrett esophagus and esophageal adenocarcinoma tissues.

“…46 β-catenin, which was reduced at the mRNA level in this study, has a pattern of progressive loss of membranous protein expression with, in some studies, an increase in nuclear accumulation. [47][48][49][50][51][52] Variable findings have been reported for EGFR (epidermal growth factor receptor) expression 53 or amplification, 54 but the progressive reduction in EGFR expression in this study, together with the failure to identify significant differences in EGFR protein expression in normal, BE and EAC tissues in another study, 47 raise doubts regarding the applicability of EGFR-targeted therapy for this cancer type. 55 Another monoclonal antibody target, HER-2/erbB-2, was the most stably expressed gene in this study, with very similar mRNA levels in normal, BE and EAC tissues.…”

Expression of α-methylacyl coenzyme A racemase in the dysplasia carcinoma sequence associated with Barrett’s esophagus

“…[18][19][20] CD1a has also been tested as a possible biomarker of Barrett's metaplasia, in the hope that its expression might help in predicting the prognosis of this pathology. 21 The markers p53 and c-erbB2 in particular have been controversially discussed.…”

Molecular biomarkers and ablative therapies for Barrett’s esophagus

“…However, this study did not find a link between p53 and increased risk (OR = 2.99; 95% CI = 0.57-15.76). In contrast, another case control study compared 35 patients with Barrett's esophagus who progressed to either esophageal adenocarcinoma or HGD [60] with 163 controls matched for age, sex and date of diagnosis of Barrett's esophagus. With mean follow up of 3.7 years the authors were unable to establish a relationship between cyclin D1 over-expression and cancer risk.…”

“…Unfortunately, however, although overexpression of p53 protein is frequently considered to be a surrogate marker for p53 mutations, it has been shown to have a high false-negative and false-positive (>25%) rate in esophageal cancer, compared to DNA sequencing [59]. Furthermore, even though Murray et al (2006) showed immunohistochemical detection of p53 protein over-expression is associated with an increased risk of progression to cancer, the sensitivity of this marker was too low to be useful for informing endoscopic surveillance strategies [60]. Reid et al (2001) published the only large study looking at p53 and Barrett's esophagus [61].…”