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Barrett’s Esophagus


Clonal Genetic Diversity and its Correlation
to Cancer Risk in Barrett’s Esophagus Barrett’s esophagus [BE] is a condition
caused by repeated exposure to stomach acid, which results in lesions. About 10% of patients experiencing chronic
acid reflux will develop Barrett’s esophagus, in turn increasing their risk of developing
esophageal cancer. Although less than 5% of patients with Barrett’s
esophagus will develop esophageal cancer, it is important to determine which patients
are at risk so that early detection and treatment can be possible. We hope to be able to determine whether or
not a given patient has an elevated risk of eventually contracting esophageal cancer by
performing a single test focusing on specific biomarkers. In order to address this goal, a group of
researchers in The Netherlands, led by Pierre Martinez and Margriet Timmer, studied how
clonal expansion and diversity might contribute to cancer risk in BE patients. Samples of cells from esophageal lesions were
collected from 320 Barrett’s patients who had received therapy for acid reflux and who
had tested negative for dysplasia. Patients were monitored for a median of 43
months, with a range of 11 to 130 months. A second endoscopy was conducted on 195 of
these patients, with a median of 37 months between the two samples. From each sample, a minimum of 50 cells were
to be counted and examined for genetic abnormalities. The samples were collected using endoscopic
brush cytology and then were examined using multicolor fluorescence in situ hybridization
analysis [FISH]. Using the FISH method, seven predetermined
genetic markers were labeled with color to identify
clonal presence, size-abundance, and diversity. Clonal expansion only occurs an average of
once every 36.8 patient years, at a rate of 1.58 cm^2 per year, translating to an average
growth rate of 0.6% of the cell population per month. Interestingly, clonal expansions were not
correlated with risk of cancer. One crucial finding of this study was that
the genetic diversity of a given lesion remains relatively stable over time, and that baseline
diversity correlates with risk of cancer. In other words, cancer risk is predetermined
by the level of diversity that exists within a patient’s cells. So, the higher the diversity, the greater
the risk, and vice-versa. A dynamic equilibrium of clonal expansions
and contractions was observed in the lesions over time. Dynamic equilibrium is maintained when there
is a normal, invariant level of genetic diversity. As a result, the rate of mutations does not
put the patient at high risk for developing cancer. When genetic diversity is high, however, dynamic
equilibrium fails to be maintained and mutations occur at an abnormal rate, increasing cancer
risk. These findings are significant because they
have indicated that it may be possible to use a single genetic diversity test to accurately
predict a BE patient’s risk of developing cancer. Because the risk of cancer remains constant
for at least 3-4 years, the test would not need to be repeated often. Diversity tests using specific markers would
allow doctors to monitor at-risk patients so that progression to cancer could be detected
early and less invasive treatments could be used, potentially increasing the patient’s
chance of survival. Dynamic equilibrium and genetic diversity
are the foundation of the naturally occurring process of evolution, which has shaped life
on Earth ever since the appearance of the first organisms. We have learned that in order for evolution
to occur, genetic variation must be present. This variation is caused by mutations, which
can disrupt the previously existing allele frequencies. Higher rates of mutation increase the likelihood
that a cell can become cancerous, explaining why increased genetic diversity is correlated
with higher risk of cancer in BE patients. If a cell develops an advantageous mutation,
it will survive to reproduce, and in the case of cancer cells, this is often at the expense
of surrounding cells. In this experiment, mutations were found in
almost every patient, often at the p16 locus. The role of this and other specific gene locations
in esophageal cancer shows how a single mutation can disrupt the entire structure of a cell,
which can in turn disrupt the functioning of the body as a whole. We may never fully understand the complexities
and implications of human genetics, but experiments like this are constantly bringing us one step
closer.

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