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Study Finds H. pylori Changes Genetically in Progression from Gastritis to Stomach Cancer

NEW YORK (GenomeWeb News) – The bacteria associated with ulcers and other stomach problems changes genetically as its human host progresses from severe gastritis to gastric cancer, according to new research.
 
Researchers from Washington University in St. Louis, the United Arab Emirates University, Sweden’s Karolinska Institute, and the Swedish Institute for Infectious Disease Control used comparative genomics and transcriptional profiling to compare the dominant Helicobacter pylori strain in one patient before and after he developed stomach cancer.
 
Their findings, which will appear this week in the Proceedings of the National Academy of Sciences, suggest H. pylori gene expression and cellular interactions change with disease progression.
 
“The degree of sequence change between the two strains was very modest,” senior author Jeffrey Gordon, director of the Center for Genome Studies at Washington University in St. Louis, told GenomeWeb Daily News. Still, they were able to pinpoint several differences in the cancer-associated isolate.
 
H. pylori is a gram-negative bacterium most commonly associated with stomach ulcers. Human hosts usually become colonized with H. pylori during childhood and without treatment retain the bug throughout their lives. It usually causes some form of gastritis, an inflammation of the stomach lining. For some, this condition can become severe, leading to the loss of the acid-producing cells called parietal cells in the stomach. In some cases, this so-called chronic atrophic gastritis is a precursor to gastric adenocarcinoma, a type of stomach cancer.
 
The team’s previous work on mouse models also suggests a small subset of H. pylori make their way into gastric progenitor — stem-cell like — cells. It’s unclear whether this happens in humans, though Gordon said there are reports of H. pylori turning up intracellularly in some tumor tissues.
 
“We’re very intrigued by this liaison between a bacteria — it’s labeled a carcinogen — and a stem cell,” Gordon says.
 
In an effort to understand how H. pylori changes with the changing gastric environment as well as the bug’s interactions with gastric stem cells, Gordon, and his colleagues used comparative genomics and gene expression profiling to compare two H. pylori samples collected from the same man four years apart. The samples were initially collected as part of the “Kalixanda” study of different endoscopic techniques, which took place in two cities in northern Sweden in the late 1990’s.
 
The team sequenced the dominant H. pylori strain found in that man’s stomach when he was first endoscopied as well as the strain present four years later when he had developed gastric cancer. “This allowed us to have a view of a very rarely captured event.” Gordon said.
 
When they sequenced the coding regions of these isolates using a Roche/454 Life Sciences GS 20 and compared them with three published H. pylori genomes, the researchers discovered subtle differences between the pre- and post- cancer genomes. As well, both lacked genes present in the reference strains.
 
They also looked at the effect of the gastric cancer H. pylori isolate on a mouse model of chronic atrophic gastritis — germ-free mice that have been genetically engineered to lack parietal cells. The H. pylori strain isolated when the patient had cancer did not colonize these mice as well. But it did invade mouse progenitor cells, something the pre-cancerous strain did not seem to do.
 
And while the genomic changes between the strains were minor, the team detected several changes in gene expression, both between the chronic atrophic gastritis and gastric cancer-associated H. pylori strains and in infected progenitor cells.
 
Using custom-designed Affymetrix GeneChips containing probesets to 1,530 of the 1,536 chromosomal genes shared between the two strains, the team compared gene expression between the H. pylori strains during mouse progenitor cell infection. In the strain isolated from the patient when he had chronic atrophic gastritis, the expression of seventeen genes changed when the bug infected progenitor cells, including genes coding for proteins involved in cell wall biosynthesis and host immune system evasion.
 
On the other hand, the expression of more than a hundred genes was altered in the cancer-associated H. pylori strain after progenitor cell infection. These included genes encoding everything from membrane proteins to proteins involved in amino acid biosynthesis and drug resistance.
 
They also detected gene expression changes in the mouse progenitor cells themselves after just a day of infection with either strain. However, infection with the cancer-associated strain ramped up the expression of genes involved in biosynthetic pathways, including polyamine biosynthesis.
 
Even so, the authors emphasized, it’s still unclear whether H. pylori is casually or causally involved in cancer development. “I think at this point it could be either — or both,” lead author Marios Giannakis, a graduate student in Gordon’s lab, told GenomeWeb Daily News.

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