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bioRxiv · 10.1101/2022.01.30.478408

AI-assisted Discovery of an Ethnicity-influenced Driver of Cell Transformation in Esophageal and Gastroesophageal Junction Adenocarcinomas

Ghosh, P.·Campos, V. J.·Vo, D. T.·Guccione, C.·Goheen-Holland, V.·Tindle, C.·Mazzini, G. S.·He, Y.·Alexandrov, L.·Lippman, S. M.·Gurski, R.·Das, S.·Curtius, K.·Yadlapati, R.·Sahoo, D.
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Abstract

Although Barretts 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{leftrightarrow}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 SUMMARYEsophageal 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{leftrightarrow}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 SUMMARYBy 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.

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Ghosh, P., Campos, V. J., Vo, D. T., Guccione, C., Goheen-Holland, V., Tindle, C., Mazzini, G. S., He, Y., Alexandrov, L., Lippman, S. M., Gurski, R., Das, S., Curtius, K., Yadlapati, R., Sahoo, D.. 2022-02-01. AI-assisted Discovery of an Ethnicity-influenced Driver of Cell Transformation in Esophageal and Gastroesophageal Junction Adenocarcinomas. https://doi.org/10.1101/2022.01.30.478408

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