Helicobacter pylori DNA methyltransferases and the epigenetic field effect in cancerization

INTRODUCTION Helicobacter pylori, a Gram-negative, microaerophilic bacterium, has co-existed with humans beings as a prominent member of their gastric microbiota for approximately 105 years (Moodley et al., 2012). It infects approximately half the world’s population, and most infected individuals are asymptomatic, but histologically exhibit superficial gastritis (The EUROGAST Study Group, 1993). Only a minority of infected individuals develop gastric or duodenal ulcers that necessitate treatment. Prolonged inflammation caused by chronic (often lifelong) infection predisposes a small fraction of infected individuals to develop gastric adenocarcinoma or lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) (Passaro et al., 2002). Unfortunately, the prognosis for cases of gastric cancer is very poor, with 5-year survival rates being lower than 15% (Peek and Blaser, 2002). A mechanism for carcinogenesis ensuing from H. pylori-triggered inflammation was first proposed by Pelayo Correa (Correa, 1992; Correa and Piazuelo, 2012). Briefly, chronic inflammation causes superficial gastritis that progresses over time to multifocal atrophic gastritis (MAG), characterized by the destruction of gastric glands. This is followed by intestinal metaplasia, wherein gastric epithelium undergoes an “epithelialmesenchymal transition” and begins to exhibit an intestinal phenotype. The subsequent stage consists of dysplasia culminating in invasive carcinoma, which completes the “pre-cancerous cascade.” The final outcome is also dependent on host and pathogen genotypes, as well as environmental factors such as socioeconomic indicators, a high-salt diet, low fruit/vegetable intake and smoking (Khalifa et al., 2010). Most notably, H. pylori is the sole bacterium to be classified by the WHO as a class I carcinogen (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 1994).