Using whole-genome sequencing to contrast genomic alterations in patients with stable Barrett’s esophagus compared to patients whose Barrett’s progressed to esophageal adenocarcinoma, Paulson et al reported that DNA changes presaging esophageal cancer can be spotted years before cancer develops. The characteristic changes include rearrangements of large chunks of DNA and damage to both copies of the tumor-suppressing gene TP53. Their findings were published in Nature Communications.
“Most patients [with progression to esophageal cancer] had two ‘hits’ to TP53,” said Thomas Paulson, PhD, Senior Staff Scientist in the Grady Lab at Fred Hutchinson Cancer Research Center, 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 [whose disease] didn’t progress to cancer.”
Though the team’s ultimate goal is to improve diagnostics and screening for esophageal cancer, Dr. Paulson emphasized that this study compares the mutations and DNA changes that occurred in patients with progression to cancer to those that occurred in patients with stable, benign Barrett’s esophagus. The findings are significant and based on analysis of over 400 tissue samples, but results from this 80-patient study would need to be validated in other patient groups before they could be used clinically to predict whether other patients with Barrett’s esophagus will have progression to cancer, he said.
Finding Cancer’s Earliest Stages
In some people with long-term acid reflux, Barrett’s esophagus arises as a new type of esophageal lining that better resists the damage caused by reflux. Even though it’s often accompanied by DNA mutations, most people will never need treatment for their Barrett’s esophagus, which will remain benign and stable. But for about 5% of these patients, their condition will progress to esophageal adenocarcinoma, which is relatively rare (about 20,000 new cases are diagnosed each year in the United States) but aggressive—only 20% of patients survive 5 years past diagnosis.
“Once you progress to an advanced esophageal adenocarcinoma, treatment options are quite limited,” Dr. Paulson said. “If you can find the tumor when it’s very small, even microscopic, the treatment options are much better.” However, 95% of patients with Barrett’s esophagus will never get cancer. For them, invasive screening and preventive measures expose them to risks without benefits.
To address this, Fred Hutch researchers set up the Seattle Barrett’s Esophagus Study in the early 1980s to learn more about the condition, how it progresses, and to find any genetic characteristics that flag patients at high or low risk of progressing to cancer. Improvements in risk stratification would help doctors give patients the right amount of screening and intervention.
Previous studies of the genetics of Barrett’s esophagus and esophageal cancer focused more on changes to specific genes. To learn more, the Fred Hutch–led team undertook a sequencing study that covers the entire genome in 427 tissue samples.
Highlighting the Changes in Esophageal Cancer
The team looked at small changes that altered just a few letters of DNA, and big changes that added, removed, or moved around large swaths of DNA. First, they found that all Barrett’s esophagus is accompanied by lots of mutations, whether a patient eventually gets 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 Project Manager in the lab run by Gavin Ha, PhD.
In the researchers’ analyses, one cancer-associated gene in particular, TP53, stood out. It’s one of the most frequently mutated genes in many types of cancer, but the team found that some Barrett’s patients who didn’t have progression to cancer also had a TP53 mutation. Their deeper dive into Barrett’s esophagus DNA revealed that the idea that any TP53 alteration leads to cancer is too simplistic. Humans get two copies of each gene (one from each parent). A person can have a mutation in one copy (one “hit”) or mutations in both copies (two hits).
“Most progressors had two hits in TP53,” said Dr. Paulson. Two hits would suggest a person is at very high risk for progression from Barrett’s to cancer, though occasionally a person with one hit may also have progression, he said. Patients whose condition progressed to cancer also had TP53 mutations in larger regions of tissue, compared to the single-hit, localized lesions in patients without progression to cancer.
Looking to the Future
Although the current findings on their own aren’t enough to change diagnostic strategies for patients, the work offers important insights. Led by senior author Xiaohong Li, PhD, the group 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 patients with Barrett’s esophagus are at risk of developing cancer.
A better future for these patients will not merely rely on genetic analyses, but on new technologies that make taking biopsies easier or even unnecessary, Ms. Galipeau said. The Fred Hutch team is exploring the possibility of developing a screening test based on DNA released into the blood from Barrett’s esophagus cells that would indicate high risk of cancer, which ends up circulating in the blood. Such a test would allow doctors to evaluate patient status less invasively, using a blood draw rather than an endoscope.
The team also hopes their findings provide insights to other cancer researchers. They think that the genetic changes they spotted may reveal insight into how cells evolve to cope with stressful conditions—and how those coping mechanisms can backfire—and go beyond esophageal-specific cancer mechanisms.
"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,” Ms. Galipeau said.
Disclosure: For full disclosures of the study authors, visit nature.com.
