Photo credit: www.sciencedaily.com
Researchers from the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins University School of Medicine have made significant strides in identifying esophageal cancer and precancerous conditions. By focusing on specific biomarkers associated with gastrointestinal cancers, they devised a biomarker algorithm that, when paired with a noninvasive technique for cell collection, could offer valuable insights. This approach aims to help clinicians determine which patients may have esophageal cancer or conditions such as Barrett’s esophagus (BE) or high-grade dysplasia, traditionally assessed through an invasive endoscopy procedure requiring anesthesia.
Pending further validation, this innovative method could act as a reflex test, guiding healthcare providers on which patients should undergo endoscopy for comprehensive evaluation. The findings of this study were shared on January 17 in the American Journal of Gastroenterology.
Dr. Stephen Meltzer, the senior author of the study and professor of medicine and oncology at Johns Hopkins, emphasized the methodical approach employed to select biomarkers relevant for Barrett’s esophagus, esophageal adenocarcinoma, and high-grade dysplasia. He noted, “This represents a pioneering effort to identify biomarkers that can aid in these diagnoses.” The algorithm identified specific gene methylation patterns in USP44, TBC1D30, and NELL1, known for their roles in cancer diagnostics.
Methylation is a chemical modification that influences gene expression and is believed to contribute to cancer development. Past research has shown USP44 to be a marker for prostate, liver, and colorectal cancers, while TBC1D30 is frequently methylated in colorectal cancer cases. NELL1 has been recognized as a diagnostic marker for Barrett’s esophagus and colorectal cancer, with its hypermethylation also linked to gastric, kidney, and lung cancers.
The research team examined six datasets from the Gene Expression Omnibus database in search of biomarkers exhibiting at least 30% methylation in BE and under 5% in normal tissues. This investigation led to the identification of 30 potential biomarkers for further analysis. Subsequent lab tests using methylation-based polymerase chain reaction confirmed 12 of these markers with significantly higher methylation levels in BE as compared to normal tissues.
From the 12 selected biomarkers, researchers advanced with seven (GRAMD1B, USP44, HOXB13, A1BG, SPX, TBC1D30, and eg00720137) alongside five additional biomarkers (CDH13, FLT3, NELL1, TAC1, and SSTI) from prior studies, for a more comprehensive analysis. They first assessed these biomarkers in 21 pairs of archived normal-Barrett’s tissue samples. Then, the study expanded to include 234 nonendoscopic esophageal sponge samples collected from patients diagnosed with BE or related conditions, along with healthy control participants undergoing endoscopy at various institutions.
The sponge sampling method involved participants swallowing a small sponge encased in a gelatin capsule, which would dissolve once reaching the bottom of the esophagus, allowing the sponge to absorb cells upon retrieval. Samples were taken either just before endoscopic procedures or within three months afterward, ensuring all participants had definitive diagnoses of esophageal cancer, BE, high-grade dysplasia, or a clear biopsy result.
After dividing the samples into a training set of 199 and a test set of 35, all 12 biomarkers were tested in the training batch. The data allowed researchers to create a three-biomarker algorithm utilizing USP44, TBC1D30, and NELL1, combined with age and sex, achieving an impressive area under the curve (AUC) of nearly 0.97 for distinguishing healthy tissues from esophageal cancer and high-grade dysplasia. For identifying healthy controls against those with BE or related cancers, the AUC stood at 0.86, which experts regard as favorable.
Dr. Meltzer explains that the primary aim of the sponge-biomarker test is not to provide a definitive diagnosis but rather to indicate a patient’s need for further investigation via endoscopy based on abnormal methylation results. The rising incidence of esophageal cancer—a condition that has seen a fivefold increase in the Western population over the past four decades—emphasizes the relevance of this work. Esophageal cancer ranks as the eighth most common cancer globally and the sixth leading cause of cancer-related deaths. It is estimated that 5%-12% of individuals with gastroesophageal reflux disease (GERD) have Barrett’s esophagus, although many cases remain undiagnosed.
“There is an urgent need,” Dr. Meltzer states, “to implement large-scale screening studies utilizing these biomarkers to evaluate their effectiveness in enhancing the detection of Barrett’s esophagus and esophageal adenocarcinoma, ultimately aiming to improve patient survival rates.” This research serves as a crucial step toward that goal.
The study’s coauthors included a team from Johns Hopkins and collaborators from various institutions, including the Allegheny Health Network, Thomas Jefferson University in Philadelphia, and Previse in Baltimore, which is the manufacturer of the sponge test.
Source
www.sciencedaily.com