People with European (white) ancestry are more likely to develop forms of the cancer than African Americans; an AI (artificial intelligence-) driven study pinpoints a specific immune cell driver and a protective genetic factor. The study was supported by grants from the National Institute of Health (NIH), as well as research gift funds from the Torey Pines Foundation and a UCSD Academic Senate Grant.[1]

Esophageal adenocarcinoma 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 of the esophagus (BE), a deleterious change in cells lining the esophagus. [2]

The American Cancer Society’s estimates that, in 2022, about 20,640 new esophageal cancer cases will be diagnosed in 2022 (16,510 in men and 4,130 in women) and about 16,410 patients will die as a result of the disease (13,250 in men and 3,160 in women).

Though the cause of esophageal adenocarcinoma, which is more common among men than among women, remains unclear, cell mutations have been linked, perhaps induced by risk factors like tobacco or alcohol use or chronic damage caused by gastroesophogeal reflux disease or GERD. But the driver of these mutations has proven confounding, in part because the incidence of esophageal adenocarcinoma is disproportionate: African Americans are approximately four- to five-fold less likely to develop esophageal adenocarcinoma than people with European ancestry. They are also less likely to experience Barrett’s metaplasia.

AI-driven study
In a new study, published in the September 22, 2022 journal JCI Insight, researchers at the University of California San Diego School of Medicine, with colleagues in Brazil, used artificial intelligence-guided tools to pinpoint both a specific type of immune cell as the disease driver, and a specific genetic variation known as a SNP (single nucleotide polymorphism) that acts as a protective factor in African Americans. [1]

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SNPs represent a difference in a single DNA building block, called a nucleotide. They 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 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 the progression from BE to EAC in different cell types and tissues, confirming their findings using organoids, patient-derived biopsies and a cross-sectional study of 113 persons with Barrett’s metaplasia and esophageal adenocarcinoma.

Pinpointing the cause
The work confirmed that all esophageal adenocarcinoma’s originate from Barrett’s metaplasia and pinpointed the role of version of neutrophil, a white blood cell that acts as the immune system’s first line of defense, as the driver of cellular transformation in both esophageal adenocarcinomas and gastroesophageal junction adenocarcinoma, a rare esophageal cancer that occurs at the connection between the esophagus and stomach.

Both cancers carry poor prognoses, with an overall 5-year survival of less than 20 percent.

“This neutrophil driver was prominent in people with European (white) ancestry, but notably absent in African Americans,” said 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 adenocarcinomas.”

The authors said the findings are important because they trace the cellular continuum from a precancer state (Barrett’s metaplasia) to cancer, 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,” Ghosh explained.

“In this instance, we found that a SNP that reduces the total number of circulating neutrophils in African Americans also protects them from esophageal adenocarcinomas, a cancer whose progression is driven by neutrophils.”

Ghosh and colleagues are cautiously optimistic that neutrophil targeted therapies may emerge as potential immunotherapies in esophageal adenocarcinomas. She said researchers will continue to investigate these possibilities.

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

[1] Ghosh P, Campos VJ, Vo DT, Guccione C, Goheen-Holland V, Tindle C, Mazzini GS, He Y, Alexandrov LB, Lippman SM, Gurski RR, Das S, Yadlapati R, Curtius K, Sahoo D. AI-assisted discovery of an ethnicity-influenced driver of cell transformation in esophageal and gastroesophageal junction adenocarcinomas. JCI Insight. 2022 Sep 22;7(18):e161334. doi: 10.1172/jci.insight.161334. PMID: 36134663.
[2] Killcoyne S, Fitzgerald RC. Evolution and progression of Barrett’s oesophagus to oesophageal cancer. Nat Rev Cancer. 2021 Nov;21(11):731-741. doi: 10.1038/s41568-021-00400-x. Epub 2021 Sep 20. PMID: 34545238.

Featured image: CT images of esophageal cancer. Photo courtesy: photo is made available under the Creative Commons CC0 1.0 Universal Public Domain Dedication.

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