For the first time, scientists have systematically analysed 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 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, or gastric cancer, is the fifth most common cancer worldwide, with nearly one million new cases in 2022. It is the third leading cause of cancer-related deaths globally, especially in East Asia and South America.
Known risk factors include being overweight, smoking, and infection with Helicobacter pylori, which triggers inflammation and stomach ulcers. H. pylori infection causes around 40% of stomach cancers in the UK.
The stomach’s lining, the gastric epithelium, is composed of gastric glands or pits and contains cells capable of developing cancer. Somatic mutations accumulate throughout our lives, and new sequencing technologies allow researchers to trace these mutations back over time.
In this study, researchers sequenced 238 normal gastric gland samples from 30 people (18 with gastric cancer and 12 without) using laser capture microdissection and whole-genome sequencing.
They found that mutation rates in normal gastric glands were similar to other body cells, suggesting protection from stomach acid. But in cancer patients, some normal-appearing glands showed early changes toward cancer, with more mutations. Cancerous tissues showed far more mutations, highlighting an acceleration of mutational processes.
Notably, they found trisomy (three copies) of chromosomes 13, 18, and 20 in some stomach lining cells — a phenomenon not seen in other tissues, suggesting exposure to an unidentified mutagen.
Driver mutations in cancer-related genes were present in nearly 10% of the stomach lining by age 60, with higher proportions in patients with chronic inflammation, suggesting inflammation might fuel mutation accumulation.
This research adds critical insights into the early evolution of cancer and supports building a comprehensive mutation map across the gastrointestinal tract.
Quotes from the authors reinforce the novelty of these findings and their implications for cancer research and broader diseases possibly tied to somatic mutations.
The study is published in Nature.
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