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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 5

Peripheral neutrophilia and signatures of tumor neutrophil infiltration prognosticate risk of EAC progression.

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Peripheral neutrophilia and signatures of tumor neutrophil infiltration ...
(A) Schematic summarizing the cohort composition of a cross-sectional study that is analyzed in panels B–D. (B) Violin plots display the neutrophil (NEUT) counts in various patients within each diagnostic group shown in A. P values indicate comparison of each subgroup against the NDBE group, as determined by Welch’s t test. See Supplemental Figure 6 for other hematologic parameters. (C and D) Univariate (C) and multivariate (D) analyses model the risk of BE to EAC progression as a linear combination of sex and the indicated hematologic parameters. Coefficient of each variable (at the center) with 95% CIs (as error bars) and the P values are illustrated in the bar plot. The P value for each term tests the null hypothesis that the coefficient is equal to zero (no effect). **P ≤ 0.01; ***P ≤ 0.001. (E and F) Kaplan-Meier plots display the overall survival of patients with tumors stratified based on the high vs. low composite scores of 2 genes (FCERG3A, FCERG3B) and the high vs. low expression values of CXCL8. P values were determined by log-rank analysis. ALC, absolute lymphocyte count. PLAT, platelets.

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