Esophageal adenocarcinoma (EAC) is a type of cancer affecting the mucus-secreting glands of the lower esophagus -; the tube connecting the throat to the stomach. It is the most common form of esophageal cancer and often preceded by Barrett’s metaplasia (BE), a deleterious change in the cells lining the esophagus.
Although the cause of EAC remains unclear, cellular mutations have been linked, possibly induced by risk factors such as tobacco or alcohol consumption or chronic damage caused by gastroesophageal reflux disease or GERD. . But the driver of these mutations has been confused, in part because the incidence of CAE is disproportionate: African Americans are about four to five times less likely to develop CAE than Caucasians. They are also less likely to experience BE.
In a new study, published September 22, 2022 in the journal JCI Overviewresearchers at the University of California San Diego School of Medicine, along with colleagues in Brazil, have used artificial intelligence-guided tools to identify both a specific type of immune cell as the driver of disease and a specific genetic variation known as SNP (single nucleotide polymorphism) that acts as a protective factor in African Americans.
SNPs represent a difference in a single building block of DNA, called a nucleotide. They normally occur in 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 share 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, associate professor in the departments of Pediatrics at UC San Diego School of Medicine and Computer Science at UC San Diego Jacobs School of Engineering, used artificial intelligence and machine learning to identify progression from BE to EAC in different types of cells and tissues, confirming their findings using organoids, patient-derived biopsies, and a cross-sectional study of 113 people with BE and EAC.
The work confirmed that all EACs originate from the EB and highlighted the role of the neutrophil version, a white blood cell that acts as the immune system’s first line of defense, as a driver of cell transformation in EAC and adenocarcinoma of the gastroesophageal junction, a rare esophagus. cancer that occurs at the junction between the esophagus and the stomach.
Both cancers carry poor prognoses, with an overall 5-year survival of less than 20%.
“This neutrophil driver was predominant in Caucasians, but notably absent in African Americans,” Sahoo said. “Conversely, SNPs associated with ethnic changes in absolute neutrophil count, such as benign ethnic neutropenia characterized by lower neutrophil counts but no increased risk of infection, are common in people of African descent and may have a deterrent effect to prevent BE from becoming EAC.”
The authors said the results are important because they trace the cellular continuum from a precancerous state (BE) to cancer and clarify the roles of neutrophils and genetic variation by ethnicity.
A central challenge in genetics is understanding how changes in DNA lead to observable changes in an organism. In this case, we found that a SNP that reduces the total number of circulating neutrophils in African Americans also protects them from EAC, a cancer whose progression is driven by neutrophils.”
Pradipta Ghosh, MD, Professor, Departments of Medicine and Cellular and Molecular Medicine, UC San Diego School of Medicine
Ghosh and his colleagues are cautiously optimistic that neutrophil-targeted therapies could emerge as potential immunotherapies in EAC. She said researchers will continue to investigate these possibilities.
The study was carried out by an international team of gastroenterologists, bioinformaticians, experts in pre-cancer biology and cancer genetics, brought together under the aegis of the Institute for Network Medicine at UC San Diego. School of Medicine. The institute promotes several transdisciplinary programs that use biological networks created with AI tools from the Center for Precision Computational Systems Network to map unknown territories of disease.
University of California – San Diego
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