New study finds genetic changes in esophageal cancer patients

As we age, more and more mutations disrupt our DNA

Led by researchers at the Fred Hutchinson Cancer Research Center, a scientific team studying precancerous lesions of the esophagus, known as Barrett's esophagus, or BE, is working to answer that question

Typical changes include rearrangement of large chunks of DNA and damage to both copies of the tumor suppressor gene TP53

"Most patients who progress to esophageal cancer have two 'hit's' of TP53 (changes that can inactivate normal gene function)," said Thomas Paulson, PhD, a senior scientist in Grady's lab who co-led the project people

While the team's ultimate goal is to improve esophageal cancer diagnosis and screening, Paulson emphasized that the study compared the mutations and DNA changes that occurred in patients who progressed to the cancer with those that occurred in patients with stable benign BE

Let's go back to the early stages of cancer

In some patients with long-term acid reflux, Barrett's esophagus develops as a new type of esophageal lining that better resists damage from reflux

"Once you develop advanced esophageal adenocarcinoma, treatment options are very limited," Paulson said

However, 95% of BE patients will never get cancer

To address this question, researchers established the Seattle Barrett's Esophagus Study in the early 1980s to learn more about BE and how it develops, and to find any signs of a patient's high or low risk of developing cancer.

Because the research team has been studying patients for years, they have a long way to go to find clues before cancer strikes

Previous genetic studies of BE and esophageal cancer have focused more on changes in specific genes, but advances in technology now allow scientists to understand DNA changes outside of genes (where most of our DNA is located)

Highlights changes in esophageal cancer

The team looked at small changes that changed just a few letters in DNA, as well as large changes that added, removed or moved large bands of DNA

In the researchers' analysis, one cancer-related gene -- TP53 -- stood out

However, their in-depth study of BE DNA showed that the idea that any alteration of TP53 would cause cancer was an oversimplification

"Most progressors have two hits in TP53," Paulson said

If both copies of TP53 are disrupted in a human cell, it can be very difficult to repair the damaged DNA

Looking to the future

Although the current discovery itself is not enough to change the patient's diagnostic strategy, the work has important insights that researchers wanting to develop a biomarker test should keep in mind, as a single TP53 mutation is unlikely to help separate high-risk and low-risk patients, as say
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Led by senior author Xiaohong Li, PhD, the team is working to integrate these findings with other data, including different types of genetic analyses, to develop an algorithm that can optimize screening times and predict which BE patients are at risk for cancer
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A bright future for BE patients depends not only on genetic analysis, but also on new technologies that make biopsies easier or even unnecessary
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Paulson and the rest of the team are exploring the possibility of developing a screening test based on DNA released into the blood by BE cells, which can show a high risk of cancer circulating in the blood
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Such a test would allow doctors to assess a patient's status in a less invasive way, using a blood draw rather than an examination through the throat
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The team also hopes their findings will provide insights for other cancer researchers
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They believe that the genetic changes they discovered may reveal how cells evolved to respond to stressful conditions -- and how those coping mechanisms can backfire -- and go beyond esophagus-specific cancer mechanisms
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"We think this study highlights that when mutations occur, they usually occur in specific tissue contexts, not the cancer itself
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Somatic whole genome dynamics of precancer in Barrett's esophagus reveals features associated with disease progression