P53 and Ki-67 overexpression in gastroesophageal reflux disease - Barrett's esophagus and adenocarcinoma sequence

Abstract

Gastroesophageal reflux disease (GERD) is a major risk factor for the development of esophageal adenocarcinoma (ACE). Many molecular alterations occur in esophageal carcinogenesis, yet the exact mechanism of ACE development remains unknown. This study aims to determine p53 protein and Ki-67 expression in esophageal mucosa of patients with GERD and study the correlation between these markers and the progression from normal squamous epithelium to esophagitis, columnar epithelium with or without intestinal metaplasia and ACE. We analyzed p53 protein and Ki-67 expression in biopsies of 200 patients with GERD and 35 patients with ACE. Those biopsies were classified into five groups: (i) G1 normal squamous epithelium (58); (ii) G2 esophagitis (80); (iii) G3 columnar epitheliums without intestinal metaplasia (30); (iv) G4, columnar epitheliums with intestinal metaplasia (32); and (v) G5 ACEs (35). p53 protein overexpression was found in 7% (4) of G1, 37.5% (30) of G2, 30% (9) of G3, 62.5% (20) of G4, and 71.4% (25) of G5 (p < 0.001). Ki-67 index increased according to the severity of histopathological diagnoses. Ki67 index was 21.3 +/- 19.5% in G1, 38.8 +/- 24.9% in G2, 37.7 +/- 26.3% in G3, 52.8 +/- 24.6% in G4, and 57.1 +/- 25.1% in G5 (P < 0.001). Linear correlation between p53/Ki67 expression and the multistep progression from squamous epithelium to ACE was observed (P < 0.001 and P < 0.05). Our results indicate that overexpression of p53 and increased Ki-67 could be associated with the development and progression to ACE in patients with GERD.

SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis

“…As in the lung, homeostatic decisions can be altered by injury to induce hyperproliferative metaplasias that increase cancer risk, especially in the bladder, cervix, and esophagus [112–117]. These decisions may analogously be driven by SOX2 and SOX9, with injury-induced changes in their expression causing metaplasia.…”

Barrett’s to Oesophageal Cancer Sequence: A Model of Inflammatory-Driven Upper Gastrointestinal Cancer

“…In chronic inflammation and in carcinogenesis, p53 is often mutated and dysfunctional, leading to inactivation of its tumour-suppressive function. In the oesophagus, p53 mutational inactivation correlates with progression from BO to OAC in patient samples [60][61][62][63], and overexpression of mutated p53 is seen in OAC [64,65]. In a BO cell line, knocking down p53 and overexpressing the oncogene Ras caused malignant transformation [66].…”

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients

“…The tissue biomarkers employed in this study have been correlated with the histological grade of Barrett’s esophagus [21–24] and used as intermediate biomarkers to assess preventive interventions in BE patients [17, 19, 25, 26]. However, these markers have not been proven in large, well-designed study to predict the risk of development of high grade dysplasia or adenocarcinoma.…”