A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma

Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case-control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (> or =3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshottrade mark. The chi(2) test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy-Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43-1.08] to 1.25 (95% CI 0.73-2.16), and for BE from 0.84 (95% CI 0.52-1.30) to 1.30 (95% CI 0.85-1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Management of Barrett's esophagus in the UK: Overtreated and underbiopsied but improved by the introduction of a national randomized trial

OBJECTIVES: To assess the variation in practice of Barrett's esophagus (BE) management in comparison with accepted international guidelines before and after the introduction of a large BE randomized controlled trial (RCT) with protocols including those of tissue sampling.
DESIGN: A validated anonymized questionnaire was sent to 401 senior attending gastroenterologists asking for details of their current management of BE, especially histological sampling. Of the 228 respondents, 57 individuals (each from a different center) were in the first group to enter the ASPirin Esomeprazole (BE) Chemoprevention Trial (AspECT), and we assessed change in practice in these centers.
RESULTS: Ninety percent of specialists did not take adequate biopsies for histological diagnosis. Furthermore, 74% would consider aggressive surgical resection for prevalent cases of high-grade dysplasia in BE as their first-line choice despite the associated perioperative mortality. Ninety-two percent claim their lack of adherence to guidelines is because there is a need for stronger evidence for surveillance and medical interventions. Effect of the AspECT trial: Those clinicians in centers where the AspECT trial has started have improved adherence to ACG guidelines compared with their previous practice (P < 0.05). BE patients now get 18.8% more biopsies compared with previous practice, and 37.7% if the patient is entered into the AspECT trial (P < 0.01).
CONCLUSIONS: This large study indicates both wide variation in practice and poor compliance with guidelines. Because optimal histology is arguably the most important facet of BE management, the improvement in practice in centers taking part in the AspECT trial indicates an additional value of large international RCTs.

Cigarette Smoking Increases Risk of Barrett’s Esophagus:An Analysis of the Barrett’s and Esophageal Adenocarcinoma Consortium

Background & Aims: Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett's esophagus. We investigated whether tobacco smoking and other factors increase risk for Barrett's esophagus.

Methods: We analyzed data from 5 case-control studies included in the international Barrett's and Esophageal Adenocarcinoma Consortium. We compared data from subjects with Barrett's esophagus (n = 1059) with those from subjects with gastroesophageal reflux disease (gastroesophageal reflux disease controls, n = 1332), and population-based controls (n = 1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for Barrett's esophagus.

Results: Subjects with Barrett's esophagus were significantly more likely to have ever smoked cigarettes than the population-based controls (odds ratio [OR] = 1.67; 95% confidence interval [CI]: 1.042.67) or gastroesophageal reflux disease controls (OR = 1.61; 95% CI: 1.331.96). Increasing pack-years of smoking increased the risk for Barrett's esophagus. There was evidence of a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (95% CI: 0.250.52).

Conclusions: Cigarette smoking is a risk factor for Barrett's esophagus. The association was strengthened with increased exposure to smoking until ~20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to development of Barrett's esophagus.

Genes of the Interleukin-18 Pathway Are Associated With Susceptibility to Barrett's Esophagus and Esophageal Adenocarcinoma

To investigate the association of genetic polymorphisms of the interleukin-18 (IL-18) pathway to Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Most cases of EAC arise in a background of reflux-induced BE. Genetic influences in this pathway are poorly understood. IL-18 is a multifunctional cytokine implicated in anti-tumor immunity. A number of polymorphisms of the IL-18 and IL-18 receptor-accessory protein (IL-18RAP) genes have been reported to alter gene expression and have recently been linked to inflammatory processes and various tumors, but have not heretofore been studied in BE and EAC.

Dietary fat and meat intakes and risk of reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma

The aim of our study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data were collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (ORs) and 95% confidence intervals (95% CIs), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR = 3.54; 95% CI = 1.32-9.46) and EAC (OR = 5.44; 95% CI = 2.08-14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR = 2.79; 95% CI = 1.11-7.04; OR = 2.41; 95% CI = 1.14-5.08, respectively) and monounsaturated fat intake (OR = 2.63; 95% CI = 1.01-6.86; OR = 5.35; 95% CI = 2.14-13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR = 3.15; 95% CI = 1.38-7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR = 4.67; 95% CI = 1.71-12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies investigating the association between dietary fat and food sources of fat are needed to confirm these results.

The NAD(P)H : quinone oxidoreductase IC609T polymorphism modifies the risk of Barrett esophagus and esophageal adenocarcinoma

Purpose: The role of genetic susceptibility to esophageal adenocarcinorna and its precursor lesion Barrett esophagus has not been fully elucidated. This study investigated the effect of polymorphisms in the manganese superoxide dismutase (MnSOD) and NAD(P)H:quinone oxicloreductase 1 (NQO1) genes in modulating the risk of developing Barrett esophagus or esophageal adenocarcinoma. Methods: A total of 584 patients (146 esophagitis, 200 Barrett esophagus, 144 esophageal adenocarcinoma, and 94 controls) were genotyped for the MnSOD C14T and NQO1 C609T polymorphisms using polymerase chain reaction and restriction fragment length polymorphism analysis. Results: The NQO1 TT genotype was less common in Barrett esophagus (2.0%) and esophageal adenocarcinoma (1.4%) patients, compared with both esophagitis patients (7.6%) and controls (5.4%). After adjustment for sex, age, body mass index, reflux symptoms, and smoking status, patients with the homozygous TT genotype had a 4.5-fold decreased risk of developing Barrett esophagus (odds ratio = 0.22, 95% confidence interval = 0.07-0.76, P = 0.01) and a 6.2-fold decreased risk of esophageal adenocarcinorna (odds ratio = 0.16, 95% confidence intervals = 0.03-0.94, P = 0.04) compared with individuals with the TC and CC genotypes. No significant differences between groups were observed for the MnSOD polymorphism (P = 0.289). Conclusions: Overall, the results of this study suggest that the NQO1 TT genotype may offer protection from reflux complications such as Barrett esophagus and esophageal adenocarcinoma.

Risk factors, DNA damage, and disease progression in Barrett's esophagus

Esophageal adenocarcinoma develops on a background of Barrett's esophagus. A number of risk factors have been linked to both conditions, including gastroesophageal reflux and smoking. However, the molecular mechanisms by which these factors influence disease progression remain unclear. One possibility is that risk factors generate promutagenic DNA damage in the esophagus. The comet assay was used to measure DNA damage in esophageal (Barrett's and squamous) and gastric mucosa of Barrett's patients with (n = 24) or without (n = 50) associated adenocarcinoma or high-grade dysplasia in comparison with control patients (squamous mucosa) without Barrett's esophagus (n = 64). Patients completed a questionnaire detailing exposure to some of the known risk factors for Barrett's esophagus and adenocarcinoma. In Barrett's esophagus patients, DNA damage was higher in Barrett's mucosa compared with normal esophageal and gastric mucosa (P < 0.001). In addition, the highest quartile of DNA damage in Barrett's mucosa was associated with an increased risk (odds ratio, 9.4; 95% confidence interval, 1.1-83.4; P = 0.044) of developing adenocarcinoma or high-grade dysplasia compared with DNA damage levels in the lowest quartile. Smoking was associated with higher DNA damage in squamous epithelium in all patient groups (P < 0.01) and in Barrett's mucosa (P < 0.05) in Barrett's esophagus patients only. In controls only, current reflux was associated with higher DNA damage, whereas anti-inflammatory drug use resulted in lower levels. Collectively, these data imply a genotoxic insult to the premalignaint Barrett's mucosa that may explain the genetic instability in this tissue and the progression to adenocarcinoma. There is an indication for a role for smoking in inducing DNA damage in esophageal mucosa but an understanding of the role of reflux requires further investigation.

Score for neonatal acute physiology-II and neonatal pain predict corticospinal tract development in premature newborns

Premature infants are at risk for adverse motor outcomes, including cerebral palsy and developmental coordination disorder. The purpose of this study was to examine the relationship of antenatal, perinatal, and postnatal risk factors for abnormal development of the corticospinal tract, the major voluntary motor pathway, during the neonatal period. In a prospective cohort study, 126 premature neonates (24-32 weeks' gestational age) underwent serial brain imaging near birth and at term-equivalent age. With diffusion tensor tractography, mean diffusivity and fractional anisotropy of the corticospinal tract were measured to reflect microstructural development. Generalized estimating equation models examined associations of risk factors on corticospinal tract development. The perinatal risk factor of greater early illness severity (as measured by the Score for Neonatal Acute Physiology-II [SNAP-II]) was associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.02), even after correcting for gestational age at birth and postnatal risk factors (P = 0.009). Consistent with previous findings, neonatal pain adjusted for morphine and postnatal infection were also associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.03 and 0.02, respectively). Lessening illness severity in the first hours of life might offer potential to improve motor pathway development in premature newborns.

Mucociliary clearance in cystic fibrosis: Physiology and pharmacological treatments

The understanding of how mutations of the cystic fibrosis gene results in recurrent infection and the development of bronchiectasis is now well established. This review examines aspects of lung pathophysiology specifically, abnormal mucociliary clearance, inflammation and infection which are the basis of the daily symptoms encountered by people with cystic fibrosis. Other components of the lung epithelium and their potential contribution to cystic fibrosis disease are discussed. Therapeutic interventions which aim to target abnormal mucociliary clearance are summarized. © 2011 Elsevier Ltd.

Dietary fiber and the risk of precancerous lesions and cancer of the esophagus:a systematic review and meta-analysis

Dietary fiber has several anticarcinogenic effects and is thought to be protective against esophageal cancer. The aim of this systematic review was to quantify the association between dietary fiber and the risk of esophageal cancer by investigating histological subtypes of esophageal cancer and the stage at which fiber may influence the carcinogenic pathway. Systematic search strategies were used to identify relevant studies, and adjusted odds ratios (ORs) were combined using random-effects meta-analyses to assess the risk of cancer when comparing extreme categories of fiber intake. Ten relevant case-control studies were identified within the timeframe searched. Pooled estimates from eight studies of esophageal adenocarcinoma revealed a significant inverse association with the highest fiber intakes (OR 0.66; 95% confidence interval [CI] 0.44-0.98). Two studies also identified protective effects of dietary fiber against Barrett's esophagus. Similar, though nonsignificant, associations were observed when results from five studies of fiber intake and risk of squamous cell carcinoma were combined (OR 0.61; 95%CI 0.31-1.20). Dietary fiber is associated with protective effects against esophageal carcinogenesis, most notably esophageal adenocarcinoma. Potential methods of action include modification of gastroesophageal reflux and/or weight control.

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

Symptoms and Endoscopic Features at Barrett's Esophagus Diagnosis: Implications for Neoplastic Progression Risk

OBJECTIVES: Risk stratification of Barrett's esophagus (BE) patients based on clinical and endoscopic features may help to optimize surveillance practice for esophageal adenocarcinoma (EAC) development. The aim of this study was to investigate patient symptoms and endoscopic features at index endoscopy and risk of neoplastic progression in a large population-based cohort of BE patients.

METHODS: A retrospective review of hospital records relating to incident BE diagnosis was conducted in a subset of patients with specialized intestinal metaplasia from the Northern Ireland BE register. Patients were matched to the Northern Ireland Cancer Registry to identify progressors to EAC or esophageal high-grade dysplasia (HGD). Cox proportional hazards models were applied to evaluate the association between endoscopic features, symptoms, and neoplastic progression risk.

RESULTS: During 27,997 person-years of follow-up, 128 of 3,148 BE patients progressed to develop HGD/EAC. Ulceration within the Barrett's segment, but not elsewhere in the esophagus, was associated with an increased risk of progression (hazard ratio (HR) 1.72; 95% confidence interval (CI): 1.08–2.76). Long-segment BE carried a significant sevenfold increased risk of progression compared with short-segment BE; none of the latter group developed EAC during the study period. Conversely, the absence of reflux symptoms was associated with an increased risk of cancer progression (HR 1.61; 95% CI: 1.05–2.46).

CONCLUSIONS: BE patients presenting with a long-segment BE or Barrett's ulcer have an increased risk of progressing to HGD/EAC and should be considered for more intense surveillance. The absence of reflux symptoms at BE diagnosis is not associated with a reduced risk of malignant progression, and may carry an increased risk of progression.