VAI makes breakthrough in cancer research

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Gerd Pfeifer. Courtesy Van Andel Institute

A recent study by Van Andel Institute revealed key aspects to understanding the root of esophageal and stomach cancers. 

Scientists at Van Andel Institute (VAI) published a study that discovered oxidative stress is a link between inflammation and certain cancers.

Inflammation has long been associated with cancer as part of the body’s natural defense against infection or injury. The inflammation of tissue is the body’s attempt at combating the problem and promoting healing. 

Part of this process is the production of reactive oxygen species (ROS), also known as free radicals, unstable molecules that are a key component of normal cellular function and communication.

If the body’s inflammatory response continues longer than necessary, the result can be a buildup of excess ROS that can elevate oxidative stress, a condition often associated with disorders such as neurodegenerative disease, diabetes and hypercholesterolemia. 

Oxidative stress happens when the body’s antioxidant levels are low and is defined by an imbalance of ROS. The condition can lead to cell and tissue breakdown. 

“Our findings provide an important piece of evidence for how inflammation and oxidative stress can cause cancer,” said Gerd Pfeifer, a professor in VAI’s department of epigenetics and the study’s senior author. “The body has a good defense system that repairs DNA damage and reduces oxidative stress, but nothing is failsafe. The more we know about the precise links between inflammation and cancer, the better equipped we are to design more effective prevention strategies.” 

Using circle damage sequencing, a new technique developed by VAI that enables scientists to “break” DNA at each point where damage occurs, Pfeifer and his colleagues mapped two types of damage in DNA caused by oxidative stress. After comparing the results to mutation signatures (characteristic combinations of mutation types) of cancer genomes, they found a match. 

Damage patterns identified by Pfeifer’s team matched the mutation signatures found in cancers of the upper gastrointestinal (GI) tract, such as esophageal cancer and stomach cancer.

Upper GI cancers frequently are preceded by inflammatory precursor conditions. For example, infection with the bacterium Heliobacter pylori can damage the lining of the stomach, causing inflammation and ulcers. In the esophagus, severe acid reflux can lead to a condition called Barrett’s esophagus, in which the lining of the esophagus becomes inflamed. In both cases, long-term inflammation is associated with increased cancer risk.

The team’s findings revealed, in upper GI cancers, the oxidative stress caused by inflammation damages specific parts of the DNA. These errors prevent DNA from being copied accurately, a key hallmark of cancer.

“Our DNA is our genetic instruction manual. When the letters get scrambled, the instructions can’t be carried out properly, and the result can be cancer,” Pfeifer said.

“There has been a lot of debate over the years about exactly how inflammation and oxidative stress contribute to disease, but we didn’t have the right tools to study the link. Our new circle damage sequencing technique is allowing us to take a fresh look at old problems. I’m hopeful it will be a game-changer.”

Circle damage sequencing allows scientists to coax damaged DNA into circles, which are replicated thousands of times using a technology called polymerase chain reaction. Once they have enough DNA, scientists use next-generation sequencing to identify which DNA bases are present at the breaks.

Last year, Pfeifer’s lab used this technique to determine the mutations that give rise to melanoma result from a chemical conversion in DNA damaged by sunlight, not just a DNA copying error, as was previously believed.

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