Scientists uncover hints of a potential new cause of stomach cancer

For the first time, scientists have systematically analyzed somatic mutations in stomach lining tissue to unpick mutational processes, some of which can lead to cancer. The team also uncovered hints of a potential new cause of stomach cancer that needs further research.

Researchers at the Wellcome Sanger Institute, Broad Institute of MIT and Harvard, the University of Hong Kong, and their collaborators sequenced the whole genomes of normal stomach lining samples from people with and without gastric cancer.

The team found that despite regular exposure to the acidic contents of the stomach, the gastric lining is protected from any toxic effects. They discovered that cells with 'driver' mutations in cancer genes occupy almost 10 per cent of the gastric lining by age 60. Plus an unusual discovery that some individuals, but not all, had mutations resulting in three copies of certain chromosomes, hinting towards exposure to an unknown mutagen.

The results, published today (19 March) in Nature, add to a map of mutations in normal tissue from the gastrointestinal tract. This work enables researchers to explore fundamental mutational processes and compare mutation rates across the body, and further understanding of the earliest stages of cancer development.

Stomach cancer, also known as gastric cancer, is the fifth most common cancer worldwide, with nearly one million new cases in 2022.¹ It is the third leading cause of cancer-related deaths globally,² with the highest number of cases in East Asia and South America.

Factors that increase the risk of developing stomach cancer include being overweight, smoking and infection with the bacterium, Helicobacter pylori, which can trigger inflammation and stomach ulcers. H. pylori infection causes around 40 per cent of stomach cancers in the UK.³

The stomach contents are acidic, as it acts as a reservoir at the first stage of processing food for digestion. The layer of cells that line the stomach – the gastric epithelium – form gastric glands, or pits, and these contain the cells that can give rise to stomach cancer.

The cells in our body acquire genetic changes, known as somatic mutations, throughout our lifetime. With new DNA sequencing technologies, researchers can now analyse these mutations in normal tissues and trace them back over time, providing insights into ageing and the earliest stages of cancer development.

In a new study, Sanger Institute researchers and their collaborators set out to investigate somatic mutations within the gastric epithelium to explore the transition between normal age-related mutations, and those that go on to form stomach cancer.

The team sequenced the whole genomes of 238 samples of normal, non-cancerous gastric gland tissue from the stomachs of 30 people from Hong Kong, the United States and the UK, of whom 18 had gastric cancer and 12 did not.⁴ With laser capture microdissection, they used a laser to precisely dissect individual cells, or glands, from the stomach lining samples for genome sequencing.

The researchers found that despite regular exposure to the acidic contents of the stomach, mutations in normal gastric glands were generated at a similar rate to most cells of the body. This suggests the cells in the gastric epithelium are protected against any toxic effects of the acidic stomach contents.

However, in people with gastric cancer, some of the glands from the normal, non-cancerous stomach lining showed changes under the microscope that resembled the early stages of transitioning to cancer. These normal glands had increased numbers of mutations, which may have contributed to initiating gastric cancer. In the cancerous tissue, numbers of mutations were much higher, showing that gastric cancers massively accelerate mutations later during their development.

An unusual finding was that some of the stomach lining cells carried three copies of certain chromosomes – chromosomes 13, 18 and 20 – known as trisomy. This has not been seen in other tissues in previous studies, suggesting it is unique to the stomach. Trisomies were found multiple times in some of the individuals, but not present in others. This implies these individuals may have been exposed to an unknown, external mutagen.

The team also found that 'driver' mutations⁵ in cancer genes, many of which are known to be mutated in gastric cancer, occupy almost 10 per cent of the stomach lining by age 60. This proportion increases when patients experience severe chronic inflammation, a known risk factor for gastric cancer. Therefore this provides a question for further research into the mechanism by which chronic inflammation increases the risk of gastric cancer.

Dr Tim Coorens, first author previously at the Wellcome Sanger Institute and now at the Broad Institute of MIT and Harvard, said: "By studying somatic mutations in normal tissues, which we acquire over our lifetimes, we can explore the earliest stages of cancer development. We found that despite constant exposure to acidic stomach contents, the stomach lining is protected. However in those with gastric cancer, we see higher numbers of mutations in normal cells, resembling the earliest stages of stomach cancer. This research adds to a mutation map of the gastrointestinal tract, including the oesophagus, stomach, small intestine and colon, to compare mutation rates and mutational processes across the body."

We discovered an unusual phenomenon, where some individuals had three copies of certain chromosomes – known as trisomy – whereas others did not. We've not seen this in any other tissue, and it hints towards an unknown, external mutagen that only some of these people may have been exposed to."

Professor Suet Yi Leung, co-lead author at the University of Hong Kong

Professor Sir Mike Stratton, co-lead author at the Wellcome Sanger Institute, said: "Ten years ago, we knew very little about the fundamental processes of mutations that are occurring in our bodies. Now with advanced genome sequencing technologies, we can investigate somatic mutations in all cell types, across various normal tissues. This enables us to look back at the evolution of our cells over a lifetime, to understand the key mutational processes that can lead to cancer. At the Sanger Institute we are leading the way in investigating the causes and consequences of somatic mutations, and exploring the possibility that somatic mutations may also contribute to diseases other than cancer."