Genetic changes facilitate the switch from Barrett’s esophagus to esophageal cancer

As we grow older, more and more mutations clutter our DNA. In most cases, these do not cause any problems. However, from time to time, the switch switches and the mutated cells become cancerous. Can you see this change in time to prevent or treat cancer before it begins?

A scientific team headed by researchers at the Fred Hutchinson Cancer Research Center to study precancerous conditions in the esophagus (called Barrett’s esophagus or BE) is working to answer this question.of Works released today At Nature Communications, the team revealed that DNA changes in BE cells that herald esophageal cancer can be detected years before cancer develops.

Characteristic changes include rearrangement of large chunks of DNA and damage to both copies of tumor suppressor genes called. TP53..

“Most advanced patients [to esophageal cancer] There were two “hits” [changes that likely inactivate normal gene function] To TP53“. Grady Lab The person who co-led the project. “In these patients, the cells are changing TP53 It spread to a wider area of ​​the esophagus and lasted longer than patients who did not progress to cancer. “

Although the team’s ultimate goal is to improve the diagnosis and screening of esophageal cancer, Paulson found that mutations and DNA changes that occurred in patients with advanced cancer in this study occurred in patients with stable benign BE. Emphasized to compare with things. Although the findings are important and are based on the analysis of more than 400 tissue samples, the results of this 80-patient study are to clinically predict whether other BE patients will progress to cancer. It should be validated with other patient groups before use. Said.

Rewind the clock to the early stages of cancer

In people with long-term acid reflux disease, Barrett’s esophagus develops as a new type of esophageal intima that better resists the damage caused by reflux. Most people do not require treatment for BE and remain benign and stable, often with DNA mutations. However, for about 5% of BE patients, their condition progresses to a type of cancer called esophageal adenocarcinoma. Esophageal cancer is relatively rare (about 20,000 new cases are diagnosed each year in the United States), but it is aggressive. 20% of patients survive 5 years after diagnosis..

“When you progress to advanced esophageal adenocarcinoma, treatment options are very limited,” Paulson said. “If the tumor is very small and can be found even microscopically, the treatment options are much better.”

However, 95% of BE patients never get cancer. For them, invasive screening and precautions are at risk without benefit.

To deal with this, Fred Hatchin’s Dr. Brian Reed His team launched Seattle Barrett’s Esophageal Research in the early 1980s. He wanted to learn more about BE and how it progresses, and find genetic features that flag patients at high or low risk of developing cancer.

The ability to classify patients into risk categories, also known as risk stratification, helps physicians provide patients with the appropriate amount of screening and intervention.

The team has been studying patients for years, so they have a long runway where they can look for clues before the cancer develops.

Previous research on the genetics of BE and esophageal cancer focused on changes in specific genes, but with current technological advances, scientists are now looking at extragenic DNA changes (where most DNA is present). ) Can now be understood. To find out more, the BE team conducted a sequencing study covering all the DNA in the cells (called the genome) of 427 tissue samples.

Emphasize changes in esophageal cancer

The team looked at small changes that changed the DNA of just a few letters and large changes that added, removed, or moved large bands of DNA. Initially, they found that all BEs were associated with many mutations, regardless of whether the patient eventually developed cancer. Researchers also said that this finding supports the hypothesis that BE that precedes cancer occurs in a radically different way than BE that remains stable.

“One of the key outcomes is the number of altered genes in patients who do not progress to cancer, and people consider them to be cancer driver genes,” said the current Public Health Science Research Program Manager. Project co-leader Patty Galipeau said. Dr. Gavin HaA laboratory that helped complete a project over the years.

Researchers have analyzed that one cancer-related gene, in particular, TP53, It stood out. It encodes proteins that regulate many important cellular processes such as recognition, repair, and cell proliferation of damaged DNA.This is one of the most frequently mutated genes in all types of cancer, but the team also has some BE patients who did not progress to cancer. TP53 mutation.

But when they dig deeper into BE DNA, TP53 The changes that lead to cancer are too simple. Humans get two copies of each gene (one from each parent). A person can have a mutation in one copy (one “hit”) or a mutation in both copies (two hits).

“Most advances had two hits TP53“Paulson said. Two hits suggest a very high risk of progressing from BE to cancer, but one hit may also progress.Some patients have progressed to cancer TP53 Mutations in a larger area of ​​tissue compared to single-hit localized lesions in non-advanced patients.

For both copies of TP53 When human cells are broken, it becomes very difficult to repair damaged DNA. This leads to replication, deletion, or reshuffle of large pieces of DNA. In fact, the team found that BE cells in patients with advanced esophageal cancer were much more likely to contain these large and complex changes than cells in patients who did not.

Looking to the future

While current findings alone are not sufficient to change a patient’s diagnostic strategy, according to Galipo, the study has important insights that researchers wishing to develop biomarker tests should keep in mind.

“Technology has improved enough to detect. TP53 Mutations in very few molecules — but that may not be the right way, ”she said.

Find singles, as the group’s work shows TP53 Mutations in just a few cells are more likely to be combined with high-risk patients rather than isolating low-risk patients.

The group, led by senior author Dr. Xiaohong Li, integrates these findings with other data, including various types of genetic analysis, to optimize screening time and which BE patients are at risk of developing cancer. We are working on the development of algorithms that can predict.

Although Reed retired in early 2022, Barrett’s esophagus research using the Barrett’s esophagus annotated repository will continue with Hatch gastroenterologists. Dr. Bill Grady Steer.

According to Galipo, a better future for BE patients will depend not only on genetic analysis, but also on new techniques that facilitate or eliminate the need for biopsies. Together with Ha, she, Paulson, and other members of the team are exploring the possibility of developing screening tests based on DNA released from BE cells. (A lot of DNA is floating in our blood and most of it is released from normal cells. Ha is working on ways to characterize DNA fragments that are useful in diagnosing and monitoring cancer. One of them.) Such a test allows doctors to evaluate. Use blood draws rather than throat scopes to make the patient’s condition more invasive.

The team also hopes that their findings will provide insights to other cancer researchers. They found out how the genetic changes evolve cells to cope with stressful conditions, and how those coping mechanisms are counterproductive and transcend esophageal-specific cancer mechanisms. I think it may reveal insights about.

“I think this study emphasizes that when mutations occur, they often occur in tissue-specific situations that are not specific to the cancer itself,” Galipo said.

reference: Paulson TG, Galipeau PC, Oman KM, and others Barrett’s somatic whole-genome dynamics of precancerous esophagus reveal features associated with disease progression. Nut common.. 2022; 13: 2300. Doi: 10.1038 / s41467-022-29767-7

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