Esophageal adenocarcinoma (EAC) is a type of cancer that affects the glands that secrete mucus in 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), which is a harmful change in the cells lining the esophagus.
Although the cause of EAC remains unclear, cellular mutations have been linked, possibly due to risk factors such as tobacco, alcohol use, or chronic damage from GERD or GERD. But the driver of these mutations has proven puzzling, 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 on September 22, 2022 in the journal JCI Insightresearchers at the University of California San Diego School of Medicine, along with colleagues in Brazil, used AI-guided tools to identify a specific type of immune cell as a driver of disease, and a specific genetic variation known as a SNP (single nucleotide polymorphism) that acts as a protective factor in African Americans. .
SNPs represent a variation of a single DNA building block called a nucleotide. They occur naturally throughout a person’s DNA. Most have no effect on health or development, but some are associated with disease when many individuals share these differences who also share a predisposition to the disease.
The team led by co-authors Pradepta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine at UCSD School of Medicine, and Debashis Sahu, PhD, associate professor in the departments of pediatrics at UCSD School of Medicine and Computer Science used UCSD Jacobs School of Engineering Artificial intelligence and machine learning to identify progression from BE to EAC in different cell types and tissues, and confirm their findings using organoids, patient-derived biopsies and across a cross-sectional study of 113 people with BE and EAC.
The work confirmed that all EACs originated from BE and identified the role of a transcriptome of the neutrophil, a white blood cell that serves as the immune system’s first line of defense, as a driver of cellular transformation in both EACs and the gastro-esophageal junction adenocarcinoma, a rare esophagus. Cancer that occurs at the connection between the esophagus and stomach.
Both types of cancer carry a poor prognosis, with a 5-year survival rate of less than 20 percent.
“This neutrophil driver was prominent in Caucasians, but notably absent in African Americans,” Saho said. Conversely, polymorphisms associated with racial 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 people 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 sequence from precancerous (BE) status to cancer, and clarify the roles of neutrophils and genetic diversity by race.
“The main challenge in genetics is to understand how changes in DNA lead to changes observed in an organism,” Ghosh said. “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 development is driven by neutrophils.”
Ghosh and colleagues are cautiously optimistic that neutrophil-targeted therapies may emerge as potential immunotherapies in EACs. She said researchers will continue to investigate these possibilities.
The study was carried out by an international team of gastroenterologists, bioinformaticians, and experts in pre-cancer biology and cancer genetics, grouped under the umbrella of Network Medicine Institute at the University of California, San Diego School of Medicine. The institute supports several interdisciplinary programs that use biological networks created using artificial intelligence tools from Accurate Computational Systems Network Center To plot unknown areas of the disease.
Co-authors are: Vinicius J. Campos, Guilherme S. Mazzini, and Richard R. Gorsky, Hospital de Clínicas de Porto Alegre, Brazil; Fu, Caitlin Guccione, Fanny Johen Holland, Courtney Tindell, Yudo Hee, Ludmill B.
Funding for this research came in part from the National Institutes of Health (grants AI141630, CA100768, GM138385, T32 GM8806, AI155696, UG3TR003355, UG3TR002968, P30 CA023100, and K23 DK125266), the Torrey Pines Academic Foundation, and the University of California, San Diego (RG103468).