Purpose: The dismal outcome of esophageal cancer patients highlights the need for novel prognostic biomarkers, such as microRNAs (miRNA). Although recent studies have established the role of miRNAs in esophageal carcinoma, a comprehensive multicenter study investigating different histologic types, including squamous cell carcinoma (SCC) and adenocarcinoma with or without Barrett's, is still lacking. Experimental Design: miRNA expression was measured in cancerous and adjacent noncancerous tissue pairs collected from 100 adenocarcinoma and 70 SCC patients enrolled at four clinical centers from the United States, Canada, and Japan. Microarray-based expression was measured in a subset of samples in two cohorts and was validated in all available samples. Results: In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. When comparing cancerous tissue expression between adenocarcinoma and SCC patients, miR-194 and miR-375 were elevated in adenocarcinoma patients. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. Associations with prognosis were independent of tumor stage or nodal status, cohort type, and chemoradiation therapy. Conclusions: Our multicenter-based results highlight miRNAs involved in major histologic types of esophageal carcinoma and uncover significant associations with prognosis. Elucidating miRNAs relevant to esophageal carcinogenesis is potentially clinically useful for developing prognostic biomarkers and identifying novel drug targets and therapies.

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion , Barrett's metaplasia. Despite advances in multimodality therapy , the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis , therapy , and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia , a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations , p16 mutations , aneuploidy , and abnormal methylation resulting in stepwise changes in differentiation , proliferation , and apoptosis , allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes , may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future. (Am J Pathol 1999, 154:965-973)

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Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.

Background Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms.Methods Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m2) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender.Results The association of OA and OGJA increased directly with increasing BMI (P for trend <0.001). Compared with individuals with a BMI <25, BMI ≥40 was associated with both OA (OR 4.76, 95% CI 2.96–7.66) and OGJA (OR 3.07, 95% CI 1.89–4.99). These associations were similar when stratified by gender and GERD symptoms. There was evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk.Conclusions These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA.

Barrett’s Esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia. Barrett’s Esophagus strongly predisposes to esophageal adenocarcinoma (EAC), a tumour with a very poor prognosis. We have undertaken the first genome-wide association study on Barrett’s Esophagus, comprising 1,852 UK cases and 5,172 UK controls in discovery and 5,986 cases and 12,825 controls in the replication. Two regions were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10−9, OR(95%CI) =1.21(1.13-1.28)) and chromosome 16q24, rs9936833 (Pcombined=2.74×10−10, OR(95%CI) =1.14(1.10-1.19)). The top SNP on chromosome 6p21 is within the major histocompatibility complex, and the closest protein-coding gene to rs9936833 on chromosome 16q24 is FOXF1, which is implicated in esophageal development and structure. We found evidence that the genetic component of Barrett’s Esophagus is mediated by many common variants of small effect and that SNP alleles predisposing to obesity also increase risk for Barrett’s Esophagus.

The aim of this study was to examine the association of obesity with esophageal adenocarcinoma, and with the precursor lesions Barrett esophagus and gastroesophageal reflux disease (GERD). This case-control study included cases with GERD (n = 142), Barrett esophagus (n = 130), and esophageal adenocarcinoma (n = 57). Controls comprised 102 asymptomatic individuals. Using logistic regression methods, we compared obesity rates between cases and controls adjusting for differences in age, gender, and lifestyle risk factors. Relative to normal weight, obese individuals were at increased risk for esophageal adenocarcinoma (Odds Ratio [OR] 4.67, 95% Confidence Interval [CI] 1.27-17.9). Diets high in vitamin C were associated with a lower risk for GERD (OR 0.40, 95% CI 0.19-0.87), Barrett esophagus (OR 0.44, 95% CI 0.20-0.98), and esophageal adenocarcinoma (OR 0.21, 95% CI 0.06-0.77). For the more established risk factors, we confirmed that smoking was a significant risk factor for esophageal adenocarcinoma, and that increased liquor consumption was associated with GERD and Barrett esophagus. In light of the current obesity epidemic, esophageal adenocarcinoma incidence rates are expected to continue to increase. Successful promotion of healthy body weight and diets high in vitamin C may substantially reduce the incidence of this disease.

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