The microbiome ecosystem of Barrett's esophagus and progression to cancer - Project Summary/abstract. Esophageal adenocarcinoma (EAC) is a major cause of cancer
morbidity and mortality in the US, affecting nearly 20,000 people each year. The
known epidemiological factors associated with EAC and its precursor Barrett’s esophagus (BE) -
gastroesophageal reflux disease, smoking, and obesity - do not completely explain why EAC
has continued to increase in incidence over the past four decades. Elucidating the full repertoire
of factors that modulate the initiation and progression of EAC will advance our understanding of
EAC tumorigenesis and impact clinical management of patients with BE. Emerging evidence
suggests microbiome alterations, potentially due to antibiotics or diet changes, are possible
causative factors for BE and EAC. Exploratory studies have identified microbiome differences
between BE and EAC patients and healthy study subjects, which suggests
dysbiotic microbiomes or the presence of absence of specific oncogenic microbiome species in
the lower esophagus may mediate the initiation of BE and/or progression of BE to EAC. We
propose to use state-of-the-art computational methods to identify and characterize
both candidate dysbiotic esophageal microbiomes and candidate oncogenic microbiome
species in an existing, well-characterized cohort of patients with BE who either progressed to
EAC (n=40) or remained non-progressing and stable with benign disease (n=40). The patients
from this case-control study have previously been evaluated by whole genome sequencing of
biopsies obtained from two locations in the esophagus at each of two time points. Using an
analysis pipeline developed by Dr. Sam Minot of our group, we will identify the different
microbiome species present in these biopsies from the whole genome sequencing data. By
comparing the microbiome species present in either non-progressing patients, progressing
patients, or in both, we will be able to determine which microbiome species are associated with
BE in general and which are indicative of patients who progress to EAC. We will validate our
findings using microbiome specific digital droplet PCR analysis and in-situ hybridization. The
results of this exploratory study will inform development of a larger, prospective study examining
the direct role of the microbiome in the development of EAC. The ultimate clinical impact of this
study would be identification of an easily assayed target for determining cancer progression risk
in patients with BE, as well as suggesting means of modulating EAC risk through elimination of
the oncogenic microbe(s) or introduction of tumor suppressive microbe(s) through antibiotic or
probiotic treatments.
