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Background & Aims: Gastric cancer (GC) cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic GC. To achieve greater benefits, it is critical to select patients who are eligible for the treatment. Albeit gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of GC and stratify patients for different chemotherapy regimens, the prediction accuracy remains to be improved. More recently, adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to GC development and progression, offering potential clinical utility for diagnosis and treatment. Methods: We conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced GC and identified an RNA editing (GCRE) signature to guide GC chemotherapy, using a systematic computational approach followed by both in vitro validations and in silico validations in TCGA. Results: We found that RNA editing events alone stand as a prognostic and predictive biomarker in advanced GC. We developed a GCRE score based on the GCRE signature consisting of 50 editing sites associated with 29 genes and achieved a high accuracy (84%) of predicting patient response to chemotherapy. Of note, patients demonstrating higher editing levels of this panel of sites present a better overall response. Consistently, GC cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced GC. Conclusions: Overall, the GCRE signature reliably stratifies patients with advanced GC and predicts response from chemotherapy. ### Competing Interest Statement R.S. is an advisory board member of BMS, Merck, Eisai, Bayer, Taiho; and reports receiving honoraria for talks from MSD, Eli Lilly, BMS, Roche, Taiho and travel funding from Roche, Astra Zeneca, Taiho, Eisai and research funding from Paxman Coolers, MSD. P.T. reports receiving honoraria for travel from Illumina and research funding from Thermo Fisher, Kyowa Hakko Kirin. O.A. and L.C. are inventors in a patent application (10202003405Y) that is related to the work that is described in this manuscript. The other authors declare that they have no competing interest.

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