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Principal Investigator: Zhongren Zhou
Organization: PRE-CANCER DIAGNOSIS, LLC
Fiscal Year: 2024
Award: $398,738
Funding agency: National Cancer Institute
Summary
The incidence of esophageal adenocarcinoma (EAC) has increased 600-700% in North America since the
1980s. EAC only has 18-22% of an overall 5-year survival rate because most patients are discovered at an
advanced stage. The single major risk factor for the development of EAC is Barrett’s esophagus (BE) where
intestinal-like glandular epithelium replaces the normal squamous mucosa of the esophagus. BE affects
approximately 2-5.4%of the adult population in the United States, with 0.12% to 1.6% of BE patients progressing
to EAC annually. Most BE patients will not progress to EAC, but they will experience anxiety and fear about their
uncertain future. It is urgent to find biomarkers to identify BE patients at high-risk progressing to EAC. DNA
hypermethylation at specific genes is the best indicator and occurs early in tumorigenesis and typically increases
with tumor progression. Recently, the role of epigenetic change in the pathogenesis of BE and EAC were
extensively studied. Multiple methylation markers have been suggested to discriminate between high -risk and
low risk BE. However, the sensitivity is relatively low for clinically predicting the patients at high-risk of
progressing to EAC. Regardless of these methylation studies, the clinically useful methylation biomarkers for
predicting BE patients to progress to EAC are still missing. Pre-Cancer Diagnosis is working to address this
critical unmet need by developing a sensitive diagnostic test that will use a target DNA hypermethylation panel
to identify those BE patients with the high-risk progressing to EAC. Recently, we found that several genes with
DNA hypermethylation could identify high-risk BE patients that are progressing to EAC, which demonstrated an
extremely high sensitivity (≈100%), and specificity (≈100%). With the DNA methylation test, we could triage the
BE patients into high-risk and low-risk groups: the high-risk patients will receive early treatment including
mucosal resection or radiofrequency ablation; the low-risk patients will have a longer follow-up interval, which
will decrease the cost. The objective of this study is to validate our preliminary data and further develop a new
methylation diagnostic kit to predict high-risk BE progression to EAC. In Aim 1, we will validate the
hypermethylation genes and develop a methylation diagnostic kit that differentiate BE patients with and without
a high risk of progressing to EAC by both DNA Methylation Epic array and PCR methylation tests. In Aim 2. We
will use whole genome sequence to validate the methylation genes that can predict high -risk BE patients
progressing to EAC and then we will develop a Target Methylation panel (a diagnostic kit) for the clinical trial.
This test will identify high-risk BE patients before progressing to EAC, which is crucial for reducing the incidence
of EAC and improving patient outcomes.
Terms: <21+ years old><Abscission><Active Follow-up><Address><Adenocarcinoma of the Esophagus><Adult><Adult Human><Affect><Alleles><Allelomorphs><Anxiety><Area Under Curve><Barrett Esophagus><Barrett Syndrome><Barrett Ulcer><Biological Markers><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Clinical><Clinical Trials><Columnar Epithelial-Lined Lower Esophagus><Columnar-Lined Esophagus><Computer software><DNA><DNA Methylation><DNA methylation profiling><Data><Deoxyribonucleic Acid><Development><Diagnosis><Diagnostic Reagent Kits><Diagnostic tests><Differentiated Gene><Disease><Disorder><Early Intervention><Early treatment><Endoscopy><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Esophageal Adenocarcinoma><Esophageal mucous membrane><Excision><Extirpation><Fear><Fright><Future><General Hospitals><Genes><Hypermethylation><Incidence><Intestinal><Intestines><Methods><Methyl-Seq><MethylSeq><Methylation><Methylation sequencing><Modeling><Mucosa><Mucosal Tissue><Mucous Membrane><North America><Oncogenesis><Pathogenesis><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phase><Population><Predicting Risk><Procedures><RF ablation><Radio Frequency Ablation><Radiofrequency Ablation><Radiofrequency Interstitial Ablation><Receiver Operating Characteristics><Receiver Operator Characteristics><Removal><Research><Resolution><Risk><Risk Factors><Role><Sampling><Sensitivity and Specificity><Software><Specificity><Surgical Removal><Survival Rate><Techniques><Testing><Triage><United States><active followup><adulthood><analytical method><bio-markers><biologic marker><biomarker><bowel><cancer progression><case-controlled studies><clinical database><clinical predictors><cost><developmental><diagnostic development><diagnostic kit><diagnostic panel><diagnostic technologies><early therapy><endoscopic imaging><entire genome><epigenetically><esophageal intestinal metaplasia><esophageal mucosa><experience><follow up><follow-up><followed up><followup><forecasting risk><full genome><high risk><improved><melting><methylation biomarker><methylation marker><methylation testing><neoplasm progression><neoplastic progression><novel><patient oriented outcomes><power analysis><precancer><precancerous><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive biomarkers><predictive marker><predictive molecular biomarker><predictive risk><predicts risk><premalignant><prevent><preventing><resection><resolutions><risk prediction><risk predictions><social role><surveillance strategy><test kit><tumor progression><tumorigenesis><whole genome>