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Principal Investigator: Prasad G. Iyer
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $444,566
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Esophageal adenocarcinoma (EAC) is a lethal cancer with poor outcomes (5 year survival <20%), when
diagnosed after the onset of symptoms, but survival is excellent when diagnosed early. Intestinal metaplasia,
or Barrett’s esophagus (BE), is the only known precursor of EAC, and progresses to EAC via development of
dysplasia. EAC can be prevented by endoscopic therapy of dysplasia. Hence endoscopic screening for BE and
endoscopic surveillance to detect dysplasia and EAC are recommended. However, > 60% of prevalent BE
remains undiagnosed and 90% of all EAC cases are diagnosed outside a BE surveillance program. The major
barrier to BE screening is the invasiveness and high cost of endoscopy. Further, screening is recommended
only in those with chronic gastroesophageal reflux (GERD), despite 50% of BE/EAC patients not reporting
GERD symptoms. Endoscopic surveillance misses 33% of prevalent EAC & dysplasia, due to the patchy
distribution of dysplasia/EAC, and inadequate biopsy sampling. Hence the overall effectiveness of endoscopic
surveillance is also severely compromised.
We used reduced representation bisulfite sequencing (RRBS) to identify a panel of methylated DNA markers
(MDMs) of BE and dysplasia/EAC followed by validation. MDM panels were highly discriminant (AUCs > 0.9)
for BE and prevalent dysplasia/EAC. When assayed on esophageal cytology specimens obtained via a sponge
on string (SOS) device, BE was detected with high accuracy (AUCs 0.97-1.0) in two case control studies done
in referral populations. The FDA approved SOS device (Capnostics, Doylestown, PA) is a 25 mm polyurethane
sponge compressed in a dissolvable capsule shell, which expands into a sphere in the stomach after being
swallowed. When pulled out through the mouth via an attached string, sampling of the entire esophageal
mucosa is achieved. The nurse-administered SOS test is safe and well tolerated with high participation rates
(65%). Hence our central hypothesis is that novel discriminant MDMs assayed on esophageal cytology
specimens obtained via the SOS device will enable accurate BE and dysplasia/EAC detection, in a screening
population with and without chronic GERD. We will test this hypothesis by three specific aims.
In specific Aim 1, we will measure the positive and negative predictive value of the SOS BE test in a screening
eligible population from primary care clinics in the Mayo Health System and compare these values in those
with and without GERD. In specific Aim 2 we will identify clinical and demographic factors, particularly GERD,
influencing the accuracy a predetermined SOS BE test prediction algorithm. In Specific Aim 3, we will measure
the accuracy of MDMs for the detection of dysplasia/EAC in BE, using the SOS device.
Utilizing an innovative, minimally invasive (non-endoscopic) and molecular approach, this proposal will
favorably impact BE detection and surveillance, enabling effective treatment, and improved EAC outcomes.
Terms: <Acid Reflux><Address><Adenocarcinoma><Adenocarcinoma of the Esophagus><Age><Algorithms><Assay><BMI><BMI percentile><BMI z-score><BS-seq><Barrett Esophagus><Barrett Syndrome><Barrett Ulcer><Bioassay><Biological Assay><Biopsy Sample><Biopsy Specimen><Bisulfite-based sequencing><Body mass index><Buccal Cavity><Buccal Cavity Head and Neck><Cancers><Capsules><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Cavitas Oris><Chronic><Clinic><Clinical><Columnar Epithelial-Lined Lower Esophagus><Columnar-Lined Esophagus><Cytology><DNA><DNA Markers><DNA Methylation><DNA biomarkers><Data><Deglutition><Demographic Factors><Deoxyribonucleic Acid><Dependence><Detection><Development><Devices><Diagnosis><Diagnostic><Dysplasia><Early Diagnosis><Effectiveness><Eligibility><Eligibility Determination><Endoscopy><Esophageal Adenocarcinoma><Esophageal Dysplasia><Esophageal Intraepithelial Neoplasia><Esophageal Reflux><Esophageal mucous membrane><Esophagus><Ethnic Origin><Ethnicity><Evaluation><FDA approved><GERD><Gastro-oesophageal Reflux><Gastroesophageal Reflux><Gastroesophageal reflux disease><Health system><High grade dysplasia><Histology><Histopathology><History><Image><Individual><Intestinal Metaplasia><Laser Electromagnetic><Laser Radiation><Lasers><Malignant Adenoma><Malignant Neoplasms><Malignant Tumor><Measures><Medical center><Molecular><Mouth><Oral cavity><Ostamer><Outcome><Participant><Patients><Pellethane><Polyisocyanates><Polyurethanes><Population><Porifera><Precancerous Conditions><Predictive Value><Premalignant Condition><Premalignant State><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Protocol Screening><Quetelet index><Recommendation><Recording of previous events><Reflex><Reflex action><Research><Research Specimen><Sampling><Sensitivity and Specificity><Smoking><Specimen><Sponges><Stomach><Surveillance Program><Swallowing><Symptoms><Techniques><Testing><Tissue Sample><Uncertainty><VAV3><VAV3 gene><Validation><Work><ages><biomarker array><biomarker panel><bisulfite sequencing><bisulfite-seq><candidate biomarker><candidate marker><capsule><case-controlled studies><cohort><cost><design><designing><developmental><doubt><dyscrasia><early detection><effective therapy><effective treatment><endomicroscopy><endoscopic imaging><esophageal intestinal metaplasia><esophageal mucosa><esophagus intraepithelial neoplasia><gastric><histories><imaging><improved><innovate><innovation><innovative><malignancy><marker panel><meeting><meetings><microendoscopy><minimally invasive><molecular biomarker><molecular marker><neoplasm/cancer><novel><nursing administration><precancerous state><prediction algorithm><prevent><preventing><primary care clinic><screening><screenings><sex><validations>