Cancer of the oesophagus (known as Barrett’s esophagus or BE) are working to find an answer to this question. The team revealed in a paper published on April 28 in Nature Communications that DNA changes in BE cells that predict esophageal cancer can be detected years before cancer develops.
Large chunks of DNA have been rearranged, and both copies of a tumor-suppressing gene called TP53 have been damaged.
“The majority of 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. “When compared to patients who did not progress to cancer, cells with altered TP53 spread to larger regions of the oesophagus and persisted for longer periods of time.”
Though the team’s ultimate goal is to improve esophageal cancer diagnostics and screening, Paulson stressed that this study compares the mutations and DNA changes that occurred in patients who progressed to cancer with those that occurred in patients with stable, benign BE. While the findings are significant and based on the analysis of over 400 tissue samples, he believes that the results of this 80-patient study would need to be validated in other patient groups before they could be used clinically to predict whether other BE patients will progress to cancer.
Rewinding the clock to the earliest stages of cancer
Barrett’s oesophagus develops in some people who have long-term acid reflux as a new type of esophageal lining that better resists the damage caused by reflux. Despite the fact that it is frequently accompanied by DNA mutations, the majority of people will never require treatment for their BE, which will remain benign and stable. However, approximately 5% of BE patients will develop a type of cancer known as esophageal adenocarcinoma. Though esophageal cancer is uncommon (about 20,000 new cases are diagnosed each year in the United States), it is deadly: only 20% of patients survive five years after diagnosis.
“Once you have advanced esophageal adenocarcinoma, your treatment options are quite limited,” Paulson explained. “The treatment options are much better if you can find the tumour when it’s very small, even microscopic.”
However, 95 percent of BE patients will never develop cancer. Invasive screening and preventive measures expose them to risks while providing no benefits.
To address this, Hutch researchers established the Seattle Barrett’s Esophagus Study in the early 1980s to learn more about BE, how it progresses, and to identify any genetic markers that indicate patients who are at high or low risk of developing cancer. The ability to categorise patients into risk categories, also known as risk stratification, would allow doctors to provide patients with the appropriate level of screening and intervention.
Because the team has been studying patients for years, they have a long runway to search for clues before cancer takes off.
Previous research on the genetics of BE and esophageal cancer focused on changes to specific genes, but technological advances now allow scientists to understand DNA changes that occur outside of genes (where most of our DNA lies). To find out more, the BE team performed a sequencing study on 427 tissue samples that covered all of the DNA in a cell (known as the genome).
A better future for BE patients will rely not only on genetic analyses, but also on new technologies that make biopsies easier or even unnecessary, according to Galipeau. With Ha, Paulson, and the rest of the team are looking into the possibility of developing a screening test based on DNA released into the blood from BE cells that indicates a high risk of cancer and ends up circulating in the blood. A test like this would allow doctors to evaluate patients’ health in a less invasive manner, using a blood draw rather than a scope down the throat.
The team also hopes that their findings will help other cancer researchers. They believe that the genetic changes they discovered may shed light on how cells evolve to cope with stressful conditions – and how those coping mechanisms can backfire – and may extend beyond esophageal cancer mechanisms.
“I think this study emphasises that when mutations occur, they frequently occur in a tissue-specific context that isn’t specific to cancer,” Galipeau said.