Esophageal adenocarcinoma is a type of cancer affecting the mucus-secreting glands of the lower esophagus and is the most common form of esophageal cancer. It is often preceded by Barrett’s metaplasia, a deleterious change in cells lining the esophagus.
Though the cause of esophageal adenocarcinoma remains unclear, cell mutations have been linked, perhaps induced by risk factors like tobacco or alcohol use, or chronic damage caused by gastroesophageal reflux disease. But the driver of these mutations has proven confounding, in part because the incidence of esophageal adenocarcinoma is disproportionate: Black Americans are approximately four- to fivefold less likely to develop esophageal adenocarcinoma than White Americans. They are also less likely to experience Barrett’s metaplasia, according to a new study published by Ghosh et al in JCI Insight.
In the study, researchers at the University of California (UC) San Diego School of Medicine, alongside colleagues in Brazil, used artificial intelligence (AI)-guided tools to pinpoint both a specific type of immune cell as the disease driver, and a specific genetic variation—a single nucleotide polymorphism (SNP)—that acts as a protective factor in Black patients.
SNPs represent a difference in a single nucleotide and occur normally throughout a person’s DNA. Most have no effect on health or development, but some are associated with disease when the variations are shared by many individuals who also have a predisposition to that disease.
The team, led by co-corresponding authors Pradipta Ghosh, MD, Professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and Debashis Sahoo, PhD, an Associate Professor in the Department of Pediatrics at UC San Diego School of Medicine and the Department of Computer Science and Engineering at UC San Diego Jacobs School of Engineering, used AI and machine learning to identify the progression from Barrett’s metaplasia to University of California San Diego School of Medicine in different cell types and tissues, confirming their findings using organoids, patient-derived biopsies, and a cross-sectional study of 113 patients with Barrett’s metaplasia and esophageal adenocarcinoma.
The work confirmed that all esophageal adenocarcinomas originate from Barrett’s metaplasia and pinpointed the role of neutrophil variety as the driver of cellular transformation in both esophageal adenocarcinomas and gastroesophageal junction adenocarcinoma. Both cancers carry poor prognoses, with an overall 5-year survival of less than 20%.
“This neutrophil driver was prominent in White Americans, but notably absent in Black Americans,” said Dr. Sahoo. “Conversely, SNPs associated with ethnic changes in absolute neutrophil count, such as benign ethnic neutropenia characterized by lower numbers of neutrophils but no increased risk of infection, are common in persons of African ancestry and may act as a deterrent to prevent Barrett’s metaplasia from becoming esophageal adenocarcinoma.”
The study authors said their findings are important because they trace the cellular continuum from a precancer state (Barrett’s metaplasia) to cancer (esophageal adenocarcinoma) and clarify the roles of neutrophils and genetic variation by ethnicity.
“A central challenge in genetics is to understand how changes in DNA result in observable changes in an organism,” said Dr. Ghosh. “In this instance, we found that a SNP that reduces the total number of circulating neutrophils in Black Americans also protects them from esophageal adenocarcinomas, a cancer whose progression is driven by neutrophils.”
Dr. Ghosh and colleagues are cautiously optimistic that neutrophil targeted therapies may emerge as potential immunotherapies in esophageal adenocarcinoma. She said researchers will continue to investigate these possibilities.
Disclosure: Funding for this research came, in part, from the National Institutes of Health, the Torrey Pines Foundation, and the UC San Diego Academic Senate. For full disclosures of the study authors, visit insight.jci.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.