The microbiome ecosystem of Barrett's esophagus and progression to cancer

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.