A recent study published in Nature Communications has found that DNA changes in patients with a certain precancerous condition, known as Barrett’s esophagus or BE, can be spotted years before cancer develops. The findings, led by researchers at Fred Hutchinson Cancer Research Center in Seattle, Washington, have uncovered what they believe to be an early warning sign for esophageal cancer, potentially opening the door for preventative measures and cancer treatment before it starts.
The changes observed in the study include rearrangements of large sections of DNA along with damage to both copies of a tumor suppressor gene known as TP53.
“Most patients who progressed [to esophageal cancer] had two ‘hits’ [changes that likely inactivate normal gene function] to TP53,” said Dr. Thomas Paulson, a senior staff scientist in the Grady Lab who co-led the project. “Cells with altered TP53 had spread to larger regions of the esophagus and persisted over longer periods of time compared to patients who didn’t progress to cancer.”
While the team at Fred Hutchinson’s end goal is to improve the diagnostics and screen methods for esophageal cancer, Paulson says that this study compared the mutations and DNA changes observed in patients who progressed to esophageal cancer with those that occurred in stable, benign BE.
Paulson also said that while the team’s findings are significant, their results would need to be validated in other patient trials before they could be used in a clinical setting, where he hopes it could be used to predict whether BE patients will progress to cancer.
About Esophageal Cancer
Esophageal cancer occurs when cells in the esophagus begin to grow abnormally. These cells do not respond to normal cell growth, division, and death signals like other healthy cells do. They also don’t organize like they are supposed to.
When this happens, these cells begin to form a tumor, which can extend into the open space inside of your esophagus or even break through the layers of your esophageal wall.
Each year, about 17,000 people are diagnosed with esophageal cancer in the United States. Worldwide, esophageal cancer is the seventh most common type of malignant cancer, with nearly 500,000 cases diagnosed each year. It is also the sixth leading cause of cancer mortality, accounting for about 500,000 deaths each year.
Many factors can play a role in a patient’s risk of developing esophageal cancer. While some risk factors are more obvious, like smoking or heavy alcohol use, Paulson and his team are particularly interested in a lesser-known cause: Barrett’s esophagus.
Early Stages of Esophageal Cancer: Understanding Barrett’s Esophagus
In some people with chronic, long-term acid reflux, also known as gastroesophageal reflux disease or GERD, a condition known as Barrett’s esophagus can develop. BE is a condition in which the pink lining of the esophagus becomes damaged by frequent acid reflux. As a result, BE arises as a new type of esophageal lining that better resists the damage caused by reflux.
Although BE is often accompanied by changes to the DNA, most people with the condition will never require any treatment, as it often remains benign and stable. However, in about five percent of BE cases, their condition will progress to a kind of esophageal cancer known as esophageal adenocarcinoma. While esophageal cancer remains relatively rare in the U.S., only about 20 percent of patients survive five years after diagnosis.
“Once you progress to an advanced esophageal adenocarcinoma, treatment options are quite limited,” Paulson said. “If you can find the tumor when it’s very small, even microscopic, the treatment options are much better.”
While nearly 95 percent of BE patients will never develop cancer, for the five percent that do, the available screening methods and preventive measures expose them to risks without benefits.
To address this, researchers Fred Hutchinson put together the Seattle Barrett’s Esophagus Study in the early 1980s to learn more about BE, how it progresses, and find any genetic characteristics that flag patients at high or low risk of progressing to cancer. Having the ability to sort patients into high-risk and low-risk groups would provide doctors will valuable information as to which patients should be screened, and which could forgo the risks.
Previous studies of BE and esophageal cancer focused more on changes to specific genes, however, new advances in technology have allowed scientists to understand changes to DNA that occur outside genes (where most of our DNA lies).
To learn more about these changes, Paulson and his team examined and sequenced tissue samples from more than 427 patients, which allowed them to observe the entire genome.
Genetic Changes In Esophageal Cancer Patients
With this new set of data, Paulson and his team focused on small changes that altered only a few letters of DNA, as well as large changes that added, removed, or moved around large sections of DNA. What they observed first was that BE is often accompanied by numerous mutations, regardless of whether a patient develops cancer or not.
“One of the critical results was how many genes were altered in patients who will never go on to cancer, that people think of as cancer-driver genes,” said project co-lead Patty Galipeau, a Public Health Sciences research program manager now in Dr. Gavin Ha’s lab, who helped shepherd the years-long project to completion.
In their findings, one gene that has been previously associated with cancer stood out: TP53. TP53 encodes a protein that regulates a lot of important cellular processes, including recognizing damaged DNA, repair, and cell growth. TP53 is one of the most commonly mutated genes in nearly all types of cancers. However, the team found that even some patients with BE who did not develop cancer had a TP53 mutation.
Paulson says that the idea that a single TP53 mutation leads to cancer is too simplistic. He noted that humans have two copies of each gene, one from each parent. While a person can have one TP53 mutation, their other copy can remain untouched, which may explain why some BE patients who did not develop cancer had this mutation present.
“Most progressors had two hits in TP53,” said Paulson. Two hits refer to having both sets of TP53 mutations. This, according to Paulson, would suggest that a person with BE is at a very high risk of developing esophageal cancer. Patients who progressed from BE to esophageal cancer also had TP53 mutations in larger regions of tissue, compared to the single-hit, localized lesions in non-progressing patients.
If a patient has both copies of TP53, their cells have a much harder time repairing damaged sections of DNA. This can allow for damaged cells to duplicate or shuffle larger sections of DNA. Paulson noted that his team “saw that BE cells in patients who progressed to esophageal cancer were much more likely to contain these large, complex changes than cells from those who never progressed.”
The Future of Esophageal Cancer Treatment
As previously mentioned, the findings by Paulson and his team still need to be reviewed and duplicated in other trials to change current diagnostic strategies for BE patients. That said, their work has shed important insights that other researchers will likely keep in mind.
“Researchers who want to develop a biomarker test should keep in mind that single TP53 mutations aren’t likely to help separate high-risk and low-risk patients,” Galipeau said.
Led by the study’s senior author, Dr. Xiaohong Li, the group hopes to integrate their findings with other data to develop an algorithm that can optimize screening times and predict which BE patients are at risk of developing cancer.
“I think this study emphasizes that when mutations are happening, they’re often happening in a tissue-specific context that’s not specific to cancer itself,” Galipeau said.
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