Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Helicobacter pylori and gastric cancer.

Gastric cancer remains a major cause of cancer death worldwide. The discovery of Helicobacter pylori Helicobacter pylori and its association with gastric cancer has opened up new insights into its pathogenesis. Gastric cancer pathogenesis is the result of a complex interplay between bacterial, host and environmental factors resulting in a step wise histological progression to neoplasia. H. pylori is a major factor in the early stages of cancer development and the mechanism of action of its virulence factors are being steadily unravelled. It is also now recognised that host genetic polymorphisms also play a complex role interacting synergistically with the bacterial virulence factors. The role of H. pylori in the causation of gastric cancer also raises the possibility of cancer prevention through screening and eradication, actions which may improve outcomes in high risk populations but which may not be cost-effective in areas of low risk. Ultimately, despite the vast improvements in knowledge, as yet there has not been a corresponding improvement in terms of gastric cancer survival rates.

Ulcerative colitis, primary sclerosing cholangitis and coeliac disease: two cases and review of the literature.

The combination of ulcerative colitis, sclerosing cholangitis and coeliac disease is unusual. The two cases described here illustrate that the investigation and management of such patients can be difficult. Other diagnoses should be considered when a patient with a known pathology fails to respond to treatment. Review of the literature suggests an increased malignant potential in these patients. We conclude that patients with a combination of ulcerative colitis, sclerosing cholangitis and coeliac disease should undergo annual colonoscopic surveillance. In those with clinical deterioration and weight loss, early liver and bowel imaging should be carried out.