DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach

BACKGROUND: Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.

METHODS: The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations.

RESULTS: A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.

CONCLUSIONS: High-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.

Secretor status and Helicobacter pylori infection are independent risk factors for gastroduodenal disease

The hypothesis that non-secretors of ABO blood group antigens, a group shown to be more susceptible to certain bacterial infections, may be at greater risk of gastroduodenal disease because of increased susceptibility to Helicobacter pylori infection was investigated. Of 101 patients with symptoms of dyspepsia who were undergoing endoscopy, 32% were non-secretors (determined from Lewis blood group phenotype), 36% had endoscopically visible gastroduodenal disease (antral gastritis, gastric ulcer, erosive duodenitis, duodenal ulcer or some combination), and 58% had H pylori detected in antral biopsy specimens. Non-secretors and patients with H pylori infection were significantly more likely to have gastroduodenal disease (p = 0.02 and p = 0.002 respectively). There was, however, no significant association between secretor status and H pylori infection, logistic regression analysis confirming that these were independently associated with gastroduodenal disease. Overall, the relative risk of gastroduodenal disease for non-secretors compared with secretors was 1.9 (95% confidence intervals 1.2, 3.2). Non-secretion of ABO blood group antigens is not related to H pylori infection but is independently and significantly associated with endoscopic gastroduodenal disease. The mechanism of this remains to be explained.

Randomised controlled trial of effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux: the bristol helicobacter project

Objectives To investigate the effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux. Design Cross sectional study, followed by a randomised placebo controlled trial. Setting Seven general practices in Bristol, England. Participants 10 537 people, aged 20-59 years, with and without H pylori infection (determined by the 13C-urea breath test). Main outcome measures Prevalence of heartburn and gastro-oesophageal acid reflux at baseline and two years after treatment to eradicate H pylori infection. Results At baseline, H pylori infection was associated with increased prevalence of heartburn (odds ratio 1.14, 95% confidence interval 1.05 to 1.23) but not reflux (1.05, 0.97 to 1.14). In participants with H pylori infection, active treatment had no effect on the overall prevalence of heartburn (0.99, 0.88 to 1.12) or reflux (1.04, 0.91 to 1.19) and did not improve pre-existing symptoms of heartburn or reflux. Conclusions H pylori infection is associated with a slightly increased prevalence of heartburn but not reflux. Treatment to eradicate H pylori has no net benefit in patients with heartburn or gastro-oesophageal reflux