AI-Driven Tools Detect Immune Cell Driver and Protective Genetic Factor for Esophageal Cancer

Esophageal adenocarcinoma (EAC) is a type of cancer that affects the glands that secrete mucus from the lower esophagus -; the tube that connects 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 that line the esophagus.

Although the cause of EAC remains unclear, cellular mutations have been linked, possibly induced by risk factors such as tobacco or alcohol use or chronic damage caused by gastroesophageal reflux disease or GERD. But the driver of these mutations has proved confusing, in part because the incidence of EAC is disproportionate: African Americans are about four to five times less likely to develop EAC than Caucasians. They are also less likely to experience BE.

In a new study, published September 22, 2022 in the journal JCI intuitionresearchers at the University of California San Diego School of Medicine, with colleagues in Brazil, used AI-driven tools to pinpoint both a specific type of immune cell as the cause of the disease, and a specific genetic variation known as the SNP ( single nucleotide polymorphism) which acts as a protective factor in African Americans.

SNPs represent a difference in a single building block of DNA, called the 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-correspondent 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 come from BE and identified the role of the version of the neutrophil, a white blood cell that serves as the first line of defense of the immune system, as the engine of cell transformation in both EACs and gastroesophageal junction adenocarcinoma. , a rare esophageal adenocarcinoma cancer that occurs at the connection between the esophagus and the stomach.

Both cancers have poor predictions, with an overall 5-year survival of less than 20%.

“This neutrophil driver was prominent in Caucasians but notably absent in African Americans,” Sahoo said. “In contrast, SNPs associated with ethnic changes in absolute neutrophil counts, such as benign ethnic neutropenia characterized by fewer neutrophils but no increased risk of infection, are common in people of African descent and can act as a deterrent to prevent to BE to become EAC. “

The authors said the findings are important because they trace the cell continuum from a precancerous (BE) state to cancer and elucidate the roles of neutrophils and genetic variation by ethnicity.

A central challenge in genetics is understanding how changes in DNA translate into 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 EACs, 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 colleagues are cautiously optimistic that neutrophil-targeted therapies may emerge as potential immunotherapies in EACs. He said researchers will continue to study these possibilities.

The study was performed by an international team of gastroenterologists, bioinformaticians, pre-cancer biology experts and cancer genetics, gathered under the auspices 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 artificial intelligence tools by the Center for Precision Computational Systems Network to trace unknown disease territories.

source:

University of California – San Diego

Journal reference:

Cabbage, P., et al. (2022) AI-assisted discovery of an ethnicity-influenced cell transformation factor in esophageal and gastroesophageal junction adenocarcinomas. JCI intuition. doi.org/10.1172/jci.insight.161334.

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