Description:
Novel DNA methylation biomarkers for detection of high-grade dysplasia and esophageal or junctional adenocarcinoma
Minimally invasive methods and kits utilizing the methylation status of epigenetic markers that distinguish normal or Barrett’s esophageal samples from high grade dysplasia (HGD), esophageal adenocarcinoma (EAC), or junctional adenocarcinoma (JCA) samples
EAC is a common and lethal cancer of GI tract. It affects ~20,000 people each year in the US and is increasing in incidence. EAC arises over time from a precancerous condition called Barrett’s esophagus (BE) which can progress to high grade dysplasia (HGD) to eventually EAC. Patients with Barrett’s esophagus are monitored with upper gastrointestinal tract endoscopy every 1-3 years in order to survey for the occurrence of HGD or early EAC. There have been recent advances in the management of high-grade dysplasia (HGD) and early EAC with well tolerated curative endoscopic therapies. However, the current screening and surveillance methods for EAC and BE are suboptimal due to the cost, inconvenience and invasiveness of upper GI endoscopy. Consequently, there is a strong need for more convenient and sensitive non-endoscopic surveillance methods. To meet this need, researchers at Fred Hutchinson Cancer Center have developed a minimally invasive Methylation-Specific digital droplet PCR (MS-ddPCR) assay to distinguish normal or Barrett’s esophageal samples from high grade HGD or EAC, or JCA samples using the methylation status of epigenetic markers (e.g., cg6522, POU3F1, YPEL3, and MAFB) and logistical regression models. Early detection allows subjects to be referred for appropriate curative endoscopic resection and ablation of the esophageal HGD or EAC.
<ul>
<li>The method can be used to test a subject for the presence of high-grade dysplasia, esophageal adenocarcinoma, or junctional adenocarcinoma</li>
<li>The diagnosis can help determine course of treatment (e.g., monitoring only, moderate treatment such as radiofrequency ablation and intramucosal resection, vs aggressive or experimental treatments)</li>
<li>A panel of all four marker genes (cg6522, POU3F1, YPEL3, and MAFB) may be used, though a two-marker panel (cg6522 and POU3F1) is equally sensitive for detection of EAC</li>
</ul>
<ul>
<li>Early detection of HGD or EAC has the potential to reduce cancer incidence and EAC associated deaths respectively</li>
<li>The non-endoscopic collection device and MS ddPCR technique makes the assay easy to administer in the clinic, which reduces costs, improves convenience, and decreases risks of surveillance tests</li>
<li>ddPCR assay is advantageous since it is simpler and more affordable than other competing tests (vs. NGS for example), targeted (i.e., panel of 2, 3 or 4 loci) and allows faster detection from limited samples</li>
</ul>
EAC incidence is rapidly increasing in the United States and affects approximately 20,000 people each year. It has a poor prognosis with 5-year survival rates of less than 20%. Esoguard™ is a molecular test that has received FDA breakthrough designation, which when combined with the EsoCheck™ device, can detect BE or cancer from normal esophageal samples with ~91% sensitivity and 90% specificity by determining methylation status of two different genes (VIM, CCNA1), but was originally developed using NGS based techniques1. The Esoguard assay is not indicated for use in the surveillance of patients with Barrett’s esophagus and does not detect HGD. Thus, there is an unmet need for simpler, convenient, non-invasive and cost-effective screening and surveillance methods for detecting HGD and EAC in patients with BE.
<ul>
<li> William Grady, MD. Translational Sciences and Therapeutics Division, and Public Health Sciences Divisions; Medical Director, GI Cancer Prevention Program Clinic</li>
<li> Ming Yu, Ph.D., Translational Sciences and Therapeutics Division</li>
</ul>
Clinical <em>(Observational Study)</em>
PCT filed, patent pending
22-119_Grady_HGD-EAC Biomarkers_NCS_FHCC.pdf
Barrett’s esophagus | dysplasia | esophageal adenocarcinoma | diagnostic | sensitivity | surveillance | Esocheck | sponge | endoscopy | esophageal brushing | in-clinic |
HGS-EAC-Biomarkers-22-119