Genetic Variation Explains Racial Disparity in Esophageal Cancer Cases

Newswise – 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 often precedes Barrett’s metaplasia (BE), a damaging change in the cells that line the esophagus.

Although the cause of EAC remains unclear, cell mutations, possibly caused by risk factors such as tobacco or alcohol use, or chronic damage from gastroesophageal reflux disease or GERD, have been linked. But 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 in the journal September 22, 2022 JCI InsightResearchers from the University of California San Diego School of Medicine along with colleagues in Brazil used artificial intelligence-guided tools to identify both a specific type of immune cell as a disease driver and a specific genetic variation known as SNP (single nucleotide polymorphism). which acts as a protective factor in African Americans.

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SNPs represent a difference in a single DNA building block called a nucleotide. They are usually found throughout a person’s DNA. Most have no health or developmental implications, but some are associated with disease when the variations are shared among 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 the UC San Diego School of Medicine, and Debashis Sahoo, PhD, associate professor in the Departments of Pediatrics at the UC San Diego School of Medicine and Computer Science at the 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, and confirmed their results with organoids from patients derived biopsies and a cross-sectional study of 113 subjects with BE and EAC.

The work confirmed that all EACs originate from BE and determined the role of neutrophil release, 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 carcinoma Cancer that occurs at the junction between the esophagus and stomach.

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Both cancers have poor prognosis, with a 5-year overall survival rate of less than 20 percent.

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

The authors said the results are important because they trace the cellular continuum from precancer (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,” 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 progression is neutrophil-driven.”

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

The study was conducted by an international team of gastroenterologists, bioinformaticians, 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 funds several transdisciplinary programs that use biological networks created with AI tools from the Center for Precision Computational Systems Network to map unknown disease areas.

Co-authors are: Vinicius J. Campos, Guilherme S. Mazzini and Richard R. Gurski, Hospital de Clínicas de Porto Alegre, Brazil; Daniella T. Vo, Caitlin Guccione, Vanae Goheen-Holland, Courtney Tindle, Yudou He, Ludmil B. Alexandrov, Scott M. Lippman, Soumita Das, Rena Yadlapati, and Kit Curtius, all from UC San Diego.

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 Foundation, and the UC San Diego Academic48 Senate (RG1036) .


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