Global variation in gastroesophageal cancer

Gastric cancer, oesophageal adenocarcinoma and oesophageal squamous-cell carcinoma (gastroesophageal cancers) are major causes of cancer mortality. Outcomes remain poor, in part because these cancers are commonly diagnosed after they have become locally advanced or metastatic, when treatment is already less likely to succeed. Despite their lethality and substantial unmet need, progress to understand their biology, and to prevent, detect, diagnose, and treat has been limited compared with many other types of cancer.

The burden of gastroesophageal cancers varies markedly across the world. Gastric cancers are especially common in East Asia, Eastern Europe and parts of South America. Oesophageal squamous-cell carcinoma reaches exceptionally high incidence across regions of East Africa, Iran and China. By contrast, the incidence of oesophageal adenocarcinoma has risen markedly over recent decades in many high-income Western populations. These striking differences point to important but poorly understood interactions between inherited susceptibility, infections and environmental exposures, tissue biology and host responses.

Gastroesophageal cancers are biologically distinct diseases and do not follow a single trajectory. Some likely arise through sequential tissue changes leading to metaplasia, dysplasia and eventually cancer. Others may not follow a clearly defined precursor pathway. In both cases this is likely due to persistent exposure, tissue injury, inflammation and altered regeneration. In addition, even where risk factors and precursor conditions are recognised, they do not reliably determine outcome. Histologically normal oesophageal squamous epithelium can contain extensive somatic clones carrying mutations in cancer-associated genes without progressing to malignancy. Furthermore, although Helicobacter pylori infection is a major risk factor for gastric cancer, only a minority of infected people develop the disease. Similarly, only a minority of people with Barrett’s oesophagus progress to oesophageal adenocarcinoma.

Conversely, many people who develop gastroesophageal cancer were not previously recognised as being at high risk. This is particularly important in oesophageal adenocarcinoma, where a high number of cancers are diagnosed outside established Barrett’s oesophagus surveillance programmes.

These observations suggest that exposure, mutational burden, clonal expansion and histological abnormality alone cannot explain who progresses to cancer. Progression may depend on interactions between the cell of origin and its state, tissue architecture, inflammatory and regenerative memory, clonal competition, immune surveillance, stromal and microbial ecosystems, ageing, inherited susceptibility and environmental exposures.

Recognising the urgent need for progress, Cancer Research UK and the Torrey Coast Foundation have partnered to launch a targeted Cancer Grand Challenges funding call on gastroesophageal cancers and seek to fund international teams capable of bringing novel approaches, technologies and thinking to tackle two major challenges.

Gastric cancer, oesophageal adenocarcinoma and oesophageal squamous-cell carcinoma display profoundly different geographical patterns of incidence. Oesophageal squamous-cell carcinoma reaches exceptionally high incidence across regions of East Africa, Iran and China. Gastric cancer is especially common in East Asia, Eastern Europe and parts of South America, while oesophageal adenocarcinoma has risen markedly in many high-income Western populations.

Known risk factors explain only part of this variation. Helicobacter pylori, tobacco, alcohol, reflux, obesity, diet and nutritional status and inherited susceptibility contribute to gastroesophageal cancer risk but do not fully account for the magnitude, distribution or changing incidence of these diseases. Decades of research into individual risk factors have not completely explained the biological mechanisms behind the contrasting global patterns of the three major gastroesophageal cancers.

This challenge seeks to move beyond descriptive epidemiology and establish the biological mechanisms through which regionally patterned exposures and host factors shape gastroesophageal cancer risk. Relevant factors could include environmental and occupational exposures (including during critical periods of life), infections, nutrition, metabolism, microbial communities, inherited susceptibility, immune fitness, tissue injury and repair, normal epithelial clonal dynamics, social determinants and sex-related biology. These examples are illustrative rather than prescriptive.

Geographical variation should be used as a natural experiment through which causal mechanisms can be distinguished from correlates of disease. Teams should integrate population-level observations with mechanistic investigations, building a “molecular epidemiological” case to determine how relevant exposures or host factors alter progenitor cell states, tissues and early disease trajectories. Comparing the three major gastroesophageal cancers may reveal shared mechanisms of early tumour initiation, or distinct causal pathways or factors with opposing effects across cancer types, therefore teams may choose to investigate more than one type of cancer. Teams will also need to account for differences in cancer registration, diagnostic access, anatomical and histopathological classification, and sampling issues.

Purely descriptive incidence mapping, studies of isolated candidate exposures without a route to causal understanding of early cancer initiation, or molecular profiling disconnected from population patterns will not be sufficient. Teams are encouraged to develop novel technologies where existing approaches cannot measure relevant exposures, reconstruct tissue histories or establish biological causation. Such technologies should be appropriate for use across participating regions.

Addressing this challenge will require international teams to collaborate across countries with contrasting incidence, exposures and disease subtypes. Teams should be co-developed by investigators across participating regions. Scientific leadership, governance, experimental work and analysis of samples and data should be shared across the partnership. The challenge should not solely rely on the extraction of samples to a small number of established research centres.

Why do we urgently need new ways to prevent cancers of the stomach and oesophagus? 

Cancers of the stomach and oesophagus (the food pipe) are major causes of cancer death worldwide. Worldwide, nearly 1.5 million new cases of stomach and oesophageal cancer were estimated in 2024. Together, these cancers caused more than 1 million deaths, over one in ten cancer deaths worldwide. They are often found only after they have spread, when treatment is less likely to work.  Researchers still cannot reliably predict who will develop these cancers. Nor can they fully explain why these cancers affect some populations far more than others.

Some risk factors and warning signs are known. For example, infection with the bacteria Helicobacter pylori can lead to tissue damage, which can increase stomach cancer risk. Barrett's oesophagus, a condition where the lining of the lower food pipe changes, can sometimes lead to oesophageal cancer. But most people with these risk factors never develop cancer, while many people who do develop cancer were not previously thought to be at high risk. Known risk factors therefore do not tell the whole story.

Cancer Research UK and the Torrey Coast Foundation are asking international teams to tackle two connected questions: what drives the earliest tissue changes towards cancer? And what causes the striking differences in cancer rates around the world? Answering these questions could make it possible to identify risk more accurately and prevent these cancers.