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AI-assisted discovery of an ethnicity-influenced driver of cell transformation in esophageal and gastroesophageal junction adenocarcinomas
Pradipta Ghosh, … , Kit Curtius, Debashis Sahoo
Pradipta Ghosh, … , Kit Curtius, Debashis Sahoo
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(18):e161334. https://doi.org/10.1172/jci.insight.161334.
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Research Article Gastroenterology Immunology

AI-assisted discovery of an ethnicity-influenced driver of cell transformation in esophageal and gastroesophageal junction adenocarcinomas

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Abstract

Although Barrett’s metaplasia of the esophagus (BE) is the only known precursor lesion to esophageal adenocarcinomas (EACs), drivers of cellular transformation in BE remain incompletely understood. We use an artificial intelligence–guided network approach to study EAC initiation and progression. Key predictions are subsequently validated in a human organoid model, in patient-derived biopsy specimens of BE, a case-control study of genomics of BE progression, and in a cross-sectional study of 113 patients with BE and EACs. Our model classified healthy esophagus from BE and BE from EACs in several publicly available gene expression data sets (n = 932 samples). The model confirmed that all EACs must originate from BE and pinpointed a CXCL8/IL8↔neutrophil immune microenvironment as a driver of cellular transformation in EACs and gastroesophageal junction adenocarcinomas. This driver is prominent in White individuals but is notably absent in African Americans (AAs). Network-derived gene signatures, independent signatures of neutrophil processes, CXCL8/IL8 expression, and an absolute neutrophil count (ANC) are associated with risk of progression. SNPs associated with changes in ANC by ethnicity (e.g., benign ethnic neutropenia [BEN]) modify that risk. Findings define a racially influenced immunological basis for cell transformation and suggest that BEN in AAs may be a deterrent to BE→EAC progression.

Authors

Pradipta Ghosh, Vinicius J. Campos, Daniella T. Vo, Caitlin Guccione, Vanae Goheen-Holland, Courtney Tindle, Guilherme S. Mazzini, Yudou He, Ludmil B. Alexandrov, Scott M. Lippman, Richard R. Gurski, Soumita Das, Rena Yadlapati, Kit Curtius, Debashis Sahoo

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Figure 7

Ethnic neutropenia may reduce the risk of transformation in BE.

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Ethnic neutropenia may reduce the risk of transformation in BE.
(A) Sche...
(A) Schematic summarizing the ligands that bind the RBC-localized DARC/ACKR1 scavenger and the impact of the African polymorphism on RBC-specific loss of DARC. (B) Global prevalence of the African Duffy-null polymorphism that causes BEN. (C and D) The prevalence of malaria (C) and the age-adjusted incidence of esophageal cancers (D) are displayed side by side. Black interrupted circles (C and D) highlight how Africans in Duffy-null zones (see B) are protected from Plasmodium vivax (C, bottom) but not from P. falciparum (C, top). (E) Summary and working model. Left: A vicious IL-8↔neutrophilic storm may be critical for driving the metaplasia–dysplasia cascade during NE→BE→EAC progression. Because of the AA Duffy-null polymorphism that manifests as neutropenia and low IL8, some races or ethnicities (e.g., AA, Hispanic/Latino) are protected. Right: As for what permits NE→BE transition, a epithelium intrinsic mechanism may be triggered by suppressed expression of Spt6 in the setting of acid, which, in turn, stalls tp63 function and expression, and a resultant loss in keratinocyte cell fate and gain in metaplastic features. These epithelium-intrinsic mechanisms are likely to be fueled by the vicious IL-8↔neutrophilic storm. HGD, high-grade dysplasia; LGD, low-grade dysplasia.

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ISSN 2379-3708

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