As we age, more and more mutations blur our DNA. Mostly, these don''t cause problems. However, a switch will change, and a mutated cell becomes cancerous. Can we see this shift in time to prevent or treat cancer before it starts?
A research group led by researchers at the Fred Hutchinson Cancer Research Center is attempting to answer this question. DNA modifications in BE cells that indicate esophageal cancer can be detected years before cancer develops.
The major changes include rearrangements of large chunks of DNA and damage to both copies of the TP53, a tumor suppressing protein.
Most patients who walked [to esophageal cancer] had two hits, according to Dr. Thomas Paulson, a senior staff scientist at theGrady Lab, who led the research. Cells with alteredTP53had spread to larger sections of the esophagus, but persisted for longer periods of time than patients who did not progress to cancer.
Paulson said the aim of this study is to improve diagnostics and screening for esophageal cancer. Despite the fact that these observations are significant and are based on an analysis of over 400 tissue samples, it would be crucial to be validated in other patients groups before they could be used clinically to predict whether other BE patients will progress to cancer.
Barretts esophagus arises as a new type of esophageal lining that better resists reflux pain. However, most individuals will never receive treatment for their BE, which is often associated with DNA mutations. However, for 5% of patients with BE, their condition will progress to an esophageal adenocarcinoma. It is also dangerous: Only 20% of patients survive five years past diagnosis.
Treatment methods, according to Paulson, are quite limited if you can locate the tumor when its very small, even microscopic.
95% of patients with BE will never receive cancer. Surgical screening and preventive measures expose them to risks without benefits.
Fred HutchsDr. Brian Reidand his team led the Seattle Barretts Esophagus Study in the early 1980s. He wanted to learn more about BE, how it progresses, and to discover any genetic limitations that put patients at high or low risk of developing cancer.
The ability to sort patients into risk categories, also known as risk stratification, would be beneficial to doctors because they can provide the patient with the appropriate screening and intervention.
Because the team has studied patients for years, they have a long runway along which they can search for clues before cancer can take off.
Previous studies of BE and esophageal cancer focused more on specific genes, but advancements in technology allow scientists to understand DNA changes outside genes (where the majority of our DNA lies). The BE team conducted a sequencing study that examined all the DNA in a cell (formerly known as the genome) in 427 tissue samples.
The researchers examined small changes that altered a few letters of DNA, as well as major changes that added, removed, or moved around large chunks of DNA. First, they found that all BE is accompanied by plenty of mutations, irrespective whether a patient eventually gets cancer or not.
One of the most significant outcomes was the fact that many genes were altered in people who will never return to cancer, which people now think of as cancer-driver genes, according to the co-director of the Public Health Sciences research program. Dr. Gavin Has helped shepherd the years-long project to completion.
One cancer-associated gene, TP53, was discovered in the researchers'' analyses. It regulates a variety of important cell interactions, including discovering damaged DNA, repair, and cell growth. It is one of the most frequently mutated genes in all kinds of cancer, but it is found that some BE patients who didn''t progress to cancer also had aTP53mutation.
However, their deeper dive into BE DNA revealed that the assumption that anyTP53alteration leads to cancer is too straightforward. Humans receive two copies of each gene (one from each parent), and a person may have a mutation in one copy (one hit) or mutations in both copies (two hits).
Paulson said that two hits indicate a person is at extremely high risk for progressing from BE to cancer, although occasionally a person with one hit may also progress. TP53mutations are observed in larger tissues, compared to single-hit, localized lesions found in non-progressing patients.
If both copies ofTP53in are broken, it is very difficult for them to repair damaged DNA. This leads to duplications, deletions, or reshuffling of large pieces of DNA. In fact, the team found that BE cells in patients who advanced to esophageal cancer were much more likely to contain these enormous, complex changes than those from others who did not.
Even if the current findings on their own aren''t sufficient to improve diagnostic strategies for patients, the work has important insights that specialists who desire to develop a biomarker test should keep in mind, according to Galipeau.
Technology is improving, although you may detectTP53mutations in a very small number of molecules, but this may not be the right path to proceed, according to a consultant.
Finding a singleTP53mutation in just a few cells would be more likely to fit low-risk patients in rather than separate them, according to groups.
The group, led by senior author Dr. Xiaohong Li, is working to combine these findings with other data, including various types of genetic analyses, to develop a novel algorithm that can track screening times and predict which BE patients are at risk of developing cancer.
With Dr. Bill Grady, Hutch, the heist, though Reid retired at the start of 2022, research into Barretts esophagus using the Barretts Esophagus Annotated Repository will continue.
Genetic testing will not only make getting biopsies easier or unnecessary, according to Galipeau. Together, she and Paulson are contemplating the possibility of developing a screening test based on DNA released from BE cells that would indicate a high risk of cancer. (We are working to develop approaches to pinpoint DNA fragment signatures that might help diagnose or monitor cancer.) This approach would allow physicians to evaluate patient status less invasively, using a blood draw rather than a scope down the throat.
The researchers hope their findings will inform other cancer researchers. They believe that the genetic changes they discovered may give insight into how cells evolve to cope with stressful situations, and how those coping mechanisms can backfire and beyond esophageal-specific cancer mechanisms.
I believe this study shows that when mutations occur, they are often occurring in a tissue-specific manner, which isn''t specific to cancer itself.