Figure 1. Evolution to cancer in the chronically inflamed stomach.

A) In this diagram, every gastric stem cell niche is represented by an individual circle. Gastric mucosal inflammation is indicated by the red shading, and each metaplastic clone is demonstrated by a coloured circle. The scenario outlined in the main text is played out across the chronically inflamed stomach, driving the erratic emergence of countless numbers of clones and subclones and dividing the stomach mucosa into a mosaic of competing clones battling for space. Clones expand through gland duplication. This clonal diversification and competition scenario is driven by increasing mucosal inflammation spreading like a wave-front along the gastric mucosa (indicated by the red shading) from distal to proximal with advancing disease stages. This underpins continued selection of metaplastic clonal lineages, as shown in the consecutive panels. All coloured circles show patches of intestinal metaplasia that expand and genetically diverge with increasing disease stages (left to right).

B) Muller plot showing this branching clonal evolution scenario in the chronically inflamed stomach. With time, multiple independent metaplastic clones are initiated, which expand and compete for space in the gastric mucosa. During clonal expansion, further random mutations are inevitably acquired, some of which may drive the selection and expansion of subclones. Rare clones may progress to gastric adenocarcinoma (colours correspond to lineages shown in A).