New study identifies genetic changes in patients who progress to
esophageal cancer
Findings in precancerous Barrett's esophagus a step toward improved
screening, prevention

Date:
April 28, 2022
Source:
Fred Hutchinson Cancer Research Center
Summary:
A scientific team who studies a precancerous condition of the
esophagus (called Barrett's esophagus or BE) are working to answer
how to see genetic changes in cells before they turn cancerous. The
team revealed that DNA changes in BE cells that presage esophageal
cancer can be spotted years before cancer develops.



FULL STORY ==========================================================================
More and more mutations clutter up our DNA as we age. Mostly, these
don't cause problems. But sometimes, a switch will flip, and a mutated
cell turns cancerous. Can we see this shift in time to prevent or treat
cancer before it starts?

==========================================================================
Led by researchers at Fred Hutchinson Cancer Research Center, a scientific
team who studies a precancerous condition of the esophagus (called
Barrett's esophagus or BE) are working to answer this question. In work published April 28 in Nature Communications, the team revealed that DNA
changes in BE cells that presage 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 a tumor-suppressing gene called TP53.

"Most 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. "Cells with altered TP53 had spread to larger regions of
the esophagus and persisted over longer periods of time compared to
patients who didn't progress to cancer." Though the team's ultimate
goal is to improve diagnostics and screening for esophageal cancer,
Paulson emphasized 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 are based on analysis of over 400 tissue samples,
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 BE patients will progress to cancer, he said.

Winding back the clock to 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 BE, which will remain benign and stable. But
for about 5% of patients with BE, their condition will progress to
a kind of cancer called esophageal adenocarcinoma. Though esophageal
cancer is relatively rare (about 20,000 new cases are diagnosed each
year in the U.S.), it's aggressive: Only 20% of patients survive five
years past diagnosis.



========================================================================== "Once you progress to an advanced esophageal adenocarcinoma, treatment
options are quite limited," 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 BE will never get cancer. For them invasive screening and preventive measures expose them to risks without benefits.

To address this, Hutch researchers set up the Seattle Barrett's Esophagus
Study in the early 1980s to learn more about BE, how it progresses,
and find any genetic characteristics that flag patients at high or low
risk of progressing to cancer. The ability to sort patients into risk categories, also known as risk stratification, would help doctors give
patients the right amount of screening and intervention.

Because the team has studied patients for years, they have a long runway
along which they can hunt for clues before cancer takes off.

Previous studies of the genetics of BE and esophageal cancer focused
more on changes to specific genes, but now advances in technology allow scientists to understand DNA changes outside genes (where most of our
DNA lies). To learn more, the BE team undertook a sequencing study that
covers all the DNA in a cell (known as the 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 BE 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 program manager now in Dr. Gavin Ha's lab, who helped shepherd
the years-long project to completion.

In the researchers' analyses, one cancer-associated gene in particular,
TP53, stood out. It encodes a protein that regulates a lot of important cellular processes, including recognizing damaged DNA, repair and cell
growth. It's one of the most frequently mutated genes in all kinds of
cancer -- but the team found that some BE patients that didn't progress
to cancer also had a TP53 mutation.

However, their deeper dive into BE 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 Paulson. Two hits would
suggest a person is at very high risk for progressing from BE to
cancer, though occasionally a person with one hit may also progress,
he said. Patients who progressed to cancer also had TP53 mutations in
larger regions of tissue, compared to the single-hit, localized lesions
in non-progressing patients.

If both copies of TP53in a person's cells are broken, it's very difficult
for them to fix damaged DNA. This leads to duplications, deletions or reshuffling of large pieces of DNA. In fact, the team saw that BE cells
in patients who progressed to esophageal cancer were much more likely
to contain these large, complex changes than cells from those who never progressed.

Looking to the future Even though the current findings on their own
aren't enough to change diagnostic strategies for patients, the work has important insights that researchers who want to develop a biomarker test
should keep in mind, such as that single TP53 mutations aren't likely
to help separate high-risk and low- risk patients, Galipeau said.

Led by senior author Dr. Xiaohong Li, 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 BE patients are at risk of developing cancer.

A better future for BE patients will not merely rely on genetic
analyses, but on new technologies that make taking biopsies easier or
even unnecessary, Galipeau said. With Ha, she, Paulson and the rest of
the team are exploring the possibility of developing a screening test
based on DNA released into the blood from BE 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 a scope down the throat.

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," Galipeau said.


========================================================================== Story Source: Materials provided by
Fred_Hutchinson_Cancer_Research_Center. Original written by Sabrina
Richards. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Thomas G. Paulson, Patricia C. Galipeau, Kenji M. Oman, Carissa A.

Sanchez, Mary K. Kuhner, Lucian P. Smith, Kevin Hadi, Minita Shah,
Kanika Arora, Jennifer Shelton, Molly Johnson, Andre Corvelo,
Carlo C. Maley, Xiaotong Yao, Rashesh Sanghvi, Elisa Venturini,
Anne-Katrin Emde, Benjamin Hubert, Marcin Imielinski, Nicolas
Robine, Brian J. Reid, Xiaohong Li. Somatic whole genome dynamics
of precancer in Barrett's esophagus reveals features associated
with disease progression. Nature Communications, 2022; 13 (1)
DOI: 10.1038/s41467-022-29767-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220428103908.htm

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