Zoest, K.P.M. van

Myo9B is associated with an increased risk of Barrett's esophagus and esophageal adenocarcinoma (Article)

2012-12-01T00:00:00Z

Background. Reflux esophagitis (RE) and Barrett's esophagus (BE) are predisposing factors for development of esophageal adenocarcinoma (EAC), the solid tumor with the fastest rising incidence in the Western world. This RE-BE-EAC cascade involves multiple host factors and consequently multiple genes. Polymorphisms in the 3′ region of myosin IXB (Myo9B) are associated with chronic inflammatory gastrointestinal disorders like celiac disease and ulcerative colitis, assuming that variation in Myo9B influences the intestinal permeability. Aim. To determine esophageal expression and the genetic variation of the Myo9B gene in the RE-BE-EAC cascade. Methods. DNA from 886 Caucasian participants (198 non-reflux controls, 305 RE, 254 BE, 129 EAC) was collected for the determination of the Myo9B gene polymorphism (rs2305764). Esophageal Myo9B expression was determined on biopsies from normal, RE, BE and EAC epithelium. Results. Genotype G/G was more common in BE (p = 0.032) and EAC (p = 0.046), but not in RE (p = 0.126) compared with the control group. Cytoplasmic Myo9B expression was determined in RE, BE and EAC, but most prominent in epithelial cells of BE and EAC. Conclusions. Genetic variation of Myo9B may play a role in the etiology of BE and EAC by increasing the permeability of the epithelial barrier.

Functional single-nucleotide polymorphism of epidermal growth factor is associated with the development of Barrett's esophagus and esophageal adenocarcinoma (Article)

2012-01-01T00:00:00Z

Reflux esophagitis (RO) and Barrett's esophagus (BO) can cause esophageal adenocarcinoma (OAC). The esophageal mucosa in the RO-BO-OAC cascade is chronically exposed to gastro-esophageal reflux. Epidermal growth factor (EGF) has an important role in the protection and repair of mucosal damage, and non-physiologic levels are associated with gastrointestinal tumors. The aim is to determine the functional effect of EGF gene polymorphisms on RO, BO and OAC development. A cohort of 871 unrelated Dutch Caucasians consisted of 198 healthy controls, 298 RO patients, 246 BO patients and 129 OAC patients. The frequency of the EGF-production-associated 5′UTR A61G polymorphism was determined in these four groups. EGF immunohistochemistry was performed on BO biopsies. EGF expression was significantly lower in the G/G genotype compared with the A/G (P0.008) and A/A (P0.002) group. The G/G genotype was significantly more prevalent in RO (odds ratios (OR)2.6; 95% confidence intervals (95% CI): 1.3-5.2), BO (OR3.0; 95% CI: 1.5-6.2) and OAC (OR4.1; 95% CI: 1.8-9.7) than in controls. The G allele is associated with reduced EGF expression and increased risk for RO, BO and OAC development. This indicates that reduced mucosal protection resulting from genetically decreased EGF expression enhances esophageal tumor development.

Differential expression of the nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) for grading dysplasia in patients with Barrett's oesophagus (Article)

2011-01-01T00:00:00Z

Aims: To investigate expression of nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) as a diagnostic tool to improve grading of dysplasia in Barrett's oesophagus patients. Methods and results: Immunostaining was analysed on a total of 192 biopsy samples of 22 Barrett's patients with no dysplasia (ND), 17 with low-grade dysplasia (LGD), 20 high-grade dysplasia (HGD) and 24 with adenocarcinoma (AC). Nuclear FXR expression was observed in 15 of 22 (68%) ND cases versus none of 19 HGD; 3 of 17 (18%); LGD; 5 of 60 (8%) patients with AC (P<0.001). FXR expression was highly specific for non-dysplastic tissue. Nuclear PXR was expressed in 16 of 20 (80%) HGD cases versus two of 16 (13%) LGD cases (PPV 89%). Upon examining adjacent tissue taken from HGD and AC patients, PXR expression was high in samples of all tissue types. Conclusions: Nuclear receptors are expressed differentially during neoplastic progression, with FXR positivity being useful to distinguish ND from dysplasia and AC. PXR nuclear expression is able to separate HGD from LGD and ND. The combination of FXR and PXR also appears to have diagnostic and possibly prognostic value, but future prospective studies are required to investigate their predictive power for neoplastic progression in Barret's oesophagus.

Proton pump inhibitor therapy in gastro-oesophageal reflux disease decreases the oesophageal immune response but does not reduce the formation of DNA adducts (Article)

2008-07-01T00:00:00Z

Background: Chronic oesophageal inflammation and related oxidative stress are important in the pathogenesis of erosive oesophagitis (EO) and its malignant progression. Aim: To study the effect of proton pump inhibitors (PPIs) on oesophageal cellular immune response and oxidative damage in EO patients. Methods: Forty gastro-oesophageal reflux disease (GERD) patients [non-erosive reflux disease (NERD): 15, EO: 25] were included, after 7 days off antisuppressive drugs. EO patients were randomized to 20-mg rabeprazole once daily for either 4 or 8 weeks with baseline and follow-up endoscopy with distal oesophageal biopsies. T lymphocytes, macrophages and mast cells were quantified by immunohistochemistry. DNA adducts were measured by analysis of 8-oxo-deoxyguanosine levels. Results: Erosive oesophagitis patients had more T lymphocytes and CD8+T lymphocytes in squamous epithelium than NERD patients (P = 0.001, P = 0.002, respectively). Levels of DNA adducts between both groups were, however, not different (P = 0.99). Four- and eight-week rabeprazole treatment in EO patients resulted in a significant decrease in number of T lymphocytes and CD8+T lymphocytes (all P < 0.05). PPIs did not, however, affect levels of DNA adducts. Conclusions: Short-term PPI therapy in EO patients reduces the oesophageal cellular immune response, but does not change oxidative damage. PPI therapy may therefore not be effective in reducing the risk of oesophageal cancer in GERD patients.