FOR IMMEDIATE RELEASE
In a groundbreaking study that could revolutionize the early detection of esophageal cancer, researchers from the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins University School of Medicine have developed an innovative biomarker algorithm. This algorithm, when integrated with a noninvasive method of collecting esophageal cells, offers clinicians a promising new tool to identify patients at risk for esophageal cancer and precancerous conditions such as Barrett’s esophagus (BE) and high-grade dysplasia. Historically, diagnosing these conditions has relied on endoscopy, a procedure that can be both invasive and distressing for patients undergoing anesthesia.
The proposed method, pending further validation, may serve as a reflex diagnostic test to guide clinicians and determine which patients necessitate endoscopy for a clearer diagnosis. The significance of this research is underscored by a paper published on January 17 in the American Journal of Gastroenterology, which outlines the methodical approach taken by the researchers to identify and validate biomarkers associated with these gastrointestinal cancers.
Senior study author Dr. Stephen Meltzer, a prominent figure in the field, emphasizes the unique nature of this research. He asserts that this study is pioneering in its selection of biomarkers specifically linked to Barrett’s esophagus, esophageal adenocarcinoma, and high-grade dysplasia. The biomarkers selected include gene methylation patterns, specifically of the genes USP44, TBC1D30, and NELL1. These particular genes have gained recognition in cancer research as promising diagnostic markers in various cancers.
Methylation, while a typical chemical modification of DNA that influences gene expression, has been critically associated with tumorigenesis. Research indicates that USP44 methylation has previously been documented in prostate, liver, and colorectal cancers, while TBC1D30 is notable for its significant methylation in colorectal cancer cases. NELL1, meanwhile, has illustrated its potential as a diagnostic marker not only in Barrett’s esophagus but also in colorectal and several other cancers, including gastric and lung malignancies.
The researchers harnessed six distinct datasets from the Gene Expression Omnibus database, implementing stringent criteria to unearth biomarkers exhibiting significant discrepancies in methylation levels between BE and normal tissues. Their meticulous analysis pinpointed 30 candidate biomarkers for subsequent studies. Through laboratory testing utilizing methylation-based polymerase chain reaction techniques, 12 biomarkers emerged as having markedly elevated methylation levels in BE tissue compared to normal samples.
To elevate the study’s rigor, the researchers selected seven of these 12 biomarkers, which included GRAMD1B, USP44, HOXB13, A1BG, SPX, TBC1D30, and eg00720137, along with an additional five biomarkers from prior studies: CDH13, FLT3, NELL1, TAC1, and SSTI, for more comprehensive analyses. Their evaluations began with 21 archived tissue pairs juxtaposing normal and Barrett’s tissues. They then expanded their research to include 234 nonendoscopic esophageal sponge samples collected from patients within the Johns Hopkins network, as well as auxiliary healthcare facilities in Pittsburgh and the Netherlands.
In a strikingly noninvasive approach, participants ingested a small sponge encapsulated in a gelatin capsule, which, upon reaching the lower esophagus, would expand after the gelatin dissolved. Clinicians then retrieved the sponge through a string, allowing for the collection of esophageal cells. This technique promises a less distressing alternative to traditional endoscopic procedures, a critical consideration given the rising incidence of esophageal cancer.
The age range of study participants averaged around 65 years, with a majority being male and predominantly from the United States. Following the collection of esophageal samples, the researchers divided them into a training set of 199 samples and a test set of 35 samples. All 12 biomarkers underwent testing within the training set, leading to the design of a three-biomarker algorithm using USP44, TBC1D30, and NELL1, with distinctions made for age and sex. The newly formulated algorithm delivered remarkable results, showcasing an area under the curve (AUC) of nearly 0.97 in differentiating healthy tissue from cases of esophageal cancer and high-grade dysplasia.
Furthermore, the algorithm exhibited an impressive AUC of 0.86 in identifying healthy control patients compared to those with Barrett’s esophagus and concurrent high-grade dysplasia or esophageal cancer. Dr. Meltzer clarified that the intent behind the sponge-biomarker test is not to deliver a definitive diagnosis but rather to act as an informative step, indicating to both clinicians and patients that an endoscopic examination might be beneficial based on abnormal methylation test results.
The urgency of this research is underscored by the alarming increase in esophageal cancer rates, which have surged fivefold over the past four decades in Western populations. It is currently the eighth most common cancer and ranks as the sixth leading cause of cancer-related mortality globally. Moreover, it is estimated that about 5% to 12% of individuals suffering from gastroesophageal reflux disease may develop Barrett’s esophagus, although comprehensive data on its prevalence remains elusive.
Given that esophageal adenocarcinoma is the predominant form of esophageal cancer in the United States, the research team emphasizes the critical need for large-scale screening studies to determine the practical efficacy of their biomarker tests and improve the timely diagnosis of Barrett’s esophagus and esophageal adenocarcinoma. Their findings thus represent a pivotal step aiming to enhance patient survival rates for these severe conditions.
In summation, this innovative research not only offers a glimpse into a potential game-changing approach to cancer diagnostics but also paves the way for new methodologies in managing and treating esophageal cancer. The collaboration of experts across multiple institutions reaffirms the significance of collective effort in tackling such pressing health challenges, and the promise of further studies offers hope for advancing clinical practices moving forward.
Subject of Research: Development of a Biomarker Algorithm for Early Detection of Esophageal Cancer
Article Title: Noninvasive Biomarker Strategy For Esophageal Cancer Detection
News Publication Date: January 17
Web References: https://www.hopkinsmedicine.org/kimmel-cancer-center, https://www.hopkinsmedicine.org/som/, https://journals.lww.com/ajg/abstract/9900/discovery_of_methylated_dna_biomarkers_for.1556.aspx
References: NIH Grants CA211457, DK118250, CA287294 and contributions from Peter Nicholl and Stuart Israelson.
Image Credits: Stephen Meltzer, M.D.
Keywords: Biomarkers, Esophageal cancer, Clinical research, Gastrointestinal neoplasms, Colorectal cancer, Small samples.
