{"doi":"10.1101/2022.01.30.478408","title":"AI-assisted Discovery of an Ethnicity-influenced Driver of Cell Transformation in Esophageal and Gastroesophageal Junction Adenocarcinomas","abstract":"ABSTRACT Although Barrett’s metaplasia of the esophagus (BE) is the only known precursor lesion to esophageal adenocarcinomas (EACs), drivers of the metaplasia→dysplasia→neoplasia cascade in the esophagus remains incompletely understood. Using an AI-guided network transcriptomics approach, in which EAC initiation and progression is modeled as networks to simplify complex multi-cellular processes, we first predict cellular continuum states and disease driving processes with an unprecedented degree of precision. Key AI-guided predictions are subsequently validated in a human organoid model and patient-derived biopsies of BE, a case-control study of genomics of BE progression, and in a cross-sectional study of 113 patients with BE and EACs. We find that all EACs must originate from BE, pinpoint a CXCL8/IL8↔neutrophil immune microenvironment as a driver of cellular transformation in both EACs and gastroesophageal junction-ACs. This driver is prominent in Caucasians (Cau), but notably absent in African Americans (AAs). Network-derived gene signatures, independent signatures of neutrophil processes, CXCL8/IL8, and an absolute neutrophil count (ANC) are associated with risk of progression. SNPs associated with ethnic changes in ANC modify that risk. Thus, findings define a racially influenced immunological basis for cell transformation and suggest that benign ethnic neutropenia in AAs may serve as a deterrent to BE→EAC progression. BRIEF SUMMARY Esophageal adenocarcinoma (EAC) is a highly lethal cancer among Caucasians, while African Americans are somewhat protected; what factors drive transformation with racial disparity remain unknown. AI-enabled creation of the first computational map of neoplastic progression in the esophagus built and validated using transcriptomic datasets from diverse cohorts of human samples pinpointed CXCL8↔neutrophil tumor immune-microenvironment as a racially influenced driver of EACs and GEJ-ACs. Computational tools pinpoint a racially influenced driver of cell transformation during BE→EAC progression; in doing so, it reveals new novel biology, informs disease modeling, therapeutic strategies, and biomarkers. LAY SUMMARY By modeling diseases as networks, this work unravels a fundamental race-influenced immunologic driver of cell transformation in adenocarcinomas of the esophagus and the gastroesophageal junction.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":302998,"datarank":0.11380176598260121,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0098296888986094,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0098296888986094,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":913359,"name":"Vinicius J. Campos","orcid":"0000-0003-2115-0932","position":1,"is_corresponding":false},{"id":588906,"name":"Daniella Vo","orcid":"0000-0003-3432-2326","position":2,"is_corresponding":false},{"id":758940,"name":"Caitlin Guccione","orcid":"0000-0002-0446-1635","position":3,"is_corresponding":false},{"id":913360,"name":"Vanae Goheen-Holland","orcid":"0000-0001-7968-0683","position":4,"is_corresponding":false},{"id":552312,"name":"Courtney Tindle","orcid":"0000-0002-8356-9707","position":5,"is_corresponding":false},{"id":725564,"name":"Guilherme S. Mazzini","orcid":"0000-0003-0191-2952","position":6,"is_corresponding":false},{"id":666847,"name":"Yudou He","orcid":"0000-0001-8733-8781","position":7,"is_corresponding":false},{"id":13201,"name":"Ludmil B. Alexandrov","orcid":"0000-0003-3596-4515","position":8,"is_corresponding":false},{"id":7922,"name":"Scott M. Lippman","orcid":"0000-0002-1643-4124","position":9,"is_corresponding":false},{"id":913361,"name":"Richard R. Gurski","orcid":"0000-0002-1769-303X","position":10,"is_corresponding":false},{"id":348404,"name":"Soumita Das","orcid":"0000-0003-3895-3643","position":11,"is_corresponding":false},{"id":303660,"name":"Rena Yadlapati","orcid":"0000-0002-7872-2033","position":12,"is_corresponding":false},{"id":310990,"name":"Kit Curtius","orcid":"0000-0002-2678-0960","position":13,"is_corresponding":false},{"id":294966,"name":"Debashis Sahoo","orcid":"0000-0003-2329-8228","position":14,"is_corresponding":false},{"id":294967,"name":"Pradipta Ghosh","orcid":"0000-0002-8917-3201","position":0,"is_corresponding":true}],"reference_count":141,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:20.348385Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}