AI-driven tools identify immune cell driver and protective genetic factor for esophageal cancer

AI-driven tools identify immune cell driver and protective genetic factor for esophageal cancer

Esophageal adenocarcinoma (EAC) is a type of cancer that affects the mucus-secreting glands of the lower esophagus. the tube that connects the throat to the stomach. It is the most common form of esophageal cancer and is often preceded by Barrett's metaplasia (BE), a harmful change in the cells that line the esophagus.

Although the cause of EAC remains unclear, cell mutations have been linked, possibly caused by risk factors such as tobacco or alcohol consumption or chronic damage from gastroesophgeal reflux disease, or GERD. However, the driver of these mutations has proven 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 Insight, researchers at the University of California San Diego School of Medicine, along with colleagues in Brazil, used artificial intelligence-driven tools to determine both a specific type of immune cell, the disease driver, and a specific genetic variation known as a SNP (Single Nucleotide Polymorphism) is known and acts as a protective factor in African Americans.

SNPs represent a difference in a single building block of DNA called a nucleotide. They are usually found throughout a person's DNA. Most have no impact on health or development, but some are associated with disease when the variations are shared by many people who also have a predisposition to that disease.

The team is led by co-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 The Jacobs School of Engineering at the School of Medicine and Computer Science at UC San Diego used artificial intelligence and machine learning to identify the progression from BE to EAC in different cell types and tissues and confirmed their findings using organoids, patients' own biopsies, and a cross-sectional substudy of 113 people with BE and EAC.

The work confirmed that all EACs are derived from BE and identified the role of the version of neutrophils, a white blood cell that acts as the immune system's first line of defense, as a driver of cell transformation in both EACs and gastroesophageal junction adenocarcinoma, a rare esophageal cancer that occurs at the junction between the esophagus and stomach occurs.

The prognosis for both types of cancer is poor; the 5-year overall survival rate is less than 20 percent.

“This neutrophil driver was prominent in Caucasians but significantly absent in African Americans,” Sahoo said. “Conversely, SNPs associated with ethnic changes in absolute neutrophil count, such as benign ethnic neutropenia, which is characterized by lower neutrophil counts but no increased risk of infection, are common in individuals of African descent and may act as a deterrent to prevent BE from becoming EAC.”

The authors said the findings are important because they trace the cellular continuum from precancerous disease (BE) to cancer and clarify the role of neutrophils and genetic variation by ethnicity.

A key challenge in genetics is understanding how changes in DNA lead to observable changes in an organism. “In this case, we found that an SNP that reduces the total number of circulating neutrophils in African Americans also protects them from EACs, a cancer whose progression is controlled by neutrophils.”

Pradipta Ghosh, MD, Professor, Departments of Medicine and Cell and Molecular Medicine, UC San Diego School of Medicine

Ghosh and colleagues are cautiously optimistic that neutrophil-targeted therapies could emerge as potential immunotherapies in EACs. She said researchers will continue to study these possibilities.

The study was conducted by an international team of gastroenterologists, bioinformaticians and experts in precancer biology and cancer genetics assembled under the umbrella of the Institute for Network Medicine at the UC San Diego School of Medicine. The institute supports several transdisciplinary programs that use biological networks created with AI tools from the Center for Precision Computational Systems Network to map unknown disease areas.

Source:

University of California – San Diego

Reference:

Ghosh, P., et al. (2022) AI-assisted discovery of an ethnically influenced driver of cell transformation in esophageal and gastroesophageal junction adenocarcinomas. JCI Insight. doi.org/10.1172/jci.insight.161334.