Methylated DNA biomarker panel noninvasively detects esophageal cancer, precursors
Key takeaways:
- The researchers’ three-biomarker algorithm successfully identified esophageal cancer, BE and high-grade dysplasia vs. health tissue.
- Their method could offer a noninvasive way to detect these diseases.
A methylation biomarker panel paired with a minimally invasive sponge-capsule device identified Barrett’s esophagus, esophageal adenocarcinoma and high-grade dysplasia, according to a study published in American Journal of Gastroenterology.
“We believe this represents the first study to select biomarkers for BE, esophageal adenocarcinoma and high-grade dysplasia in this fashion,” Stephen J. Meltzer, MD, senior study author and Harry and Betty Myerberg/Thomas R. Hendrix Professor in Gastroenterology at Johns Hopkins University School of Medicine, said in a related press release.
Researchers have recently investigated the use of a sponge-capsule device to collect esophageal cells in combination with biomarkers specific to BE and esophageal adenocarcinoma (EAC) as a minimally invasive, accessible nonendoscopic strategy to screen for these diseases, improving their detection and ultimately patient survival.
“Many methylation-based BE/EAC biomarkers have been studied for detection of BE and EAC, but to deploy this diagnostic strategy effectively, a panel of biomarkers is usually needed,” Meltzer and colleagues wrote.
The researchers conducted a multisite, international, observational case-control study to validate a new model — based on a genome-wide methylation screen and the identification of biomarkers specific to BE, high-grade dysplasia and EAC — and determine its ability to detect these diseases when used with the sponge-on-a-string device.
First, they used the Gene Expression Omnibus database to search for biomarkers that were at least 30% methylated in BE but less than 5% methylated in normal tissues, according to the release. The researchers ultimately selected seven biomarkers that they identified along with five biomarkers from previous studies to further test: A1BG, C9orf50, cg00720137, FLI1, GRAMD1B, HOXB13, IRF4, KCNQ3, NTNG1, SPX, TBC1D30 and USP44.
Next, they utilized 21 matched normal tissue to BE tissue pairs to confirm that the 12 selected biomarkers were significantly hypermethylated in BE tissue DNA (all P < .05).
They then performed a case-control study of 234 patients (median age, 65 years; range, 19-87; 33% women) undergoing esophagogastroduodenoscopy for clinical indications in the U.S. (n = 164) or the Netherlands (n = 35) between 2018 and 2022. This included 78 controls, 77 patients with nondysplastic BE, 61 patients with EAC and 12 patients with BE with high-grade dysplasia.
The researchers collected patient esophageal cells using the EsophaCap device, a swallowable sponge within a dissolvable gelatin capsule with a string for retrieval, immediately before esophagogastroduodenoscopy or at follow-up within 3 months of procedure.
The researchers divided the sponge samples into a training set (n = 199) and an independent test set (n = 35), using the training set to develop a classification algorithm, the best of which was selected based on the Least Absolute Shrinkage and Selection Operator procedure. The final model consisted of a three-biomarker algorithm (USP44, TBCD1D30, NELL1), age at biopsy and sex.
Using this algorithm, the researchers successfully distinguished high-grade dysplasia or EAC samples from normal samples in the training set (area under the curve = 0.91; 95% CI, 0.86-0.96) and the test set (AUC = 0.97; 95% CI, 0.91-1).
Similarly, the algorithm was able to identify healthy patients vs. patients with nondysplastic BE, low- or high-grade dysplasia, or EAC in both sets (training: AUC = 0.86; 95% CI, 0.81-0.91; test: AUC = 0.86; 95% CI, 0.75-0.98).
Finally, when distinguishing healthy patients from patients with nondysplastic BE, the algorithm produced an AUC of 0.82 (95% CI, 0.75-0.89) in the training set and 0.78 (95% CI, 0.58-0.97) in the test set.
The researchers noted several limitations to the study, including its observational nature and that most patients were from the U.S.
“The goal with this sponge-biomarker test is not to provide a definitive diagnosis,” Meltzer said in the release. “Rather, it is to inform them that they may need an endoscopy, because their methylation test results were abnormal.
“With EAC being the leading esophageal cancer type in the U.S., there is an urgent need to apply these markers in a large-scale screening study to assess whether the test can improve detection of BE and EAC and ultimately help improve survival of these patients, which this study provides impetus for,” he added.
Reference:
- Researchers develop biomarker algorithm for noninvasive detection of Barrett's esophagus and esophageal cancer. https://www.hopkinsmedicine.org/news/newsroom/news-releases/2025/01/researchers-develop-biomarker-algorithm-for-barretts-esophagus-and-esophageal-cancer. Published Jan. 22, 2025. Accessed Jan. 29, 2025.
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