Multi-omics profiling reveals gene signatures and therapeutic targets in HER2-guided gastric cardia adenocarcinoma patients

Abstract Therapeutic targets for gastric cardia adenocarcinoma (GCA), particularly for HER2-negative patients, are lacking. Here, we conducted multi-omics profiling on 128 GCA patients using mass spectrometry, whole-exome sequencing, RNA-Seq, scRNA-Seq and spatial transcriptomics. Based on HER2 expression levels, we categorized patients into HER2-high, -low, and -negative groups and confirmed the favorable prognostic significance of HER2. We uncovered an enrichment of DNA repair features in the HER2-high group, while HER2-low and -negative groups exhibited strong inflammation. We found that tumor mutation burden may not be the distinguishing factor among these three groups. We revealed that the HER2-negative and -low groups have a tumor-suppressive immune microenvironment. Our study revealed that anti-inflammatory approaches and immune checkpoint inhibition targeting the CD47 / SIRPA axis may serve as therapeutic strategies for patients with HER2-negative GCA. These findings highlight promising avenues for personalized treatment of GCA.