“3G” Trial: An RNA Editing Signature for Guiding Gastric Cancer Chemotherapy

Abstract

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. 4 SignificanceDespite the increasing documentation of RNA editing and its functional regulation, the translational potential of RNA editome in cancer remains largely under-investigated. This study reports for the first time an RNA editing signature in advanced GC, to reliably stratify patients with advanced disease to predict response from chemotherapy independently of gene expression profiling and other genomic and epigenetic changes. For this purpose, a bioinformatics approach was used to develop a GCRE score based on a panel of 50 editing sites from 29 unique genes (GCRE signature), followed by an experimental evaluation of their clinical utility as predictive biomarker in GC cell lines and in silico validation in using RNA sequencing (RNA-Seq) datasets from TCGA. The applied methodology provides a robust means of an RNA editing signature to be investigated in patients with advanced GC. Overall, this study provides insights into the translation of RNA editing process into predictive clinical applications to direct chemotherapy against GC.

Inosine in Biology and Disease

“…The contribution of A-to-I editing to the translation of proteins of oncogenic importance is explored in cancer research for its diagnostic and therapeutic potential [ 141 , 142 ]. For instance, progression of gastric tumor from healthy tissue is associated with enhanced editing at ADAR1-specific sites and downregulation of editing at ADAR2-specific sites [ 143 ], pointing at inosine modifiers as potential biomarkers for gastric cancer [ 144 ]. Moreover, increases in ADAR1 activity through gene amplification enhance lung tumorigenesis [ 145 ], while loss of ADAR1 function allows tumor cells to overcome resistance to immunotherapy by removing the checkpoint that restrains the dsRNA-mediated immune response pathway [ 146 ].…”