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

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.胃贲门腺癌（Gastric Cardia Adenocarcinoma，GCA）的治疗靶点，尤其是人表皮生长因子受体2（HER2）阴性患者的治疗靶点，目前仍较为匮乏。本研究针对128例GCA患者，采用质谱法（mass spectrometry）、全外显子组测序（whole-exome sequencing）、RNA测序（RNA-Seq）、单细胞RNA测序（scRNA-Seq）及空间转录组学（spatial transcriptomics）开展多组学表征分析。基于HER2的表达水平，研究人员将患者划分为HER2高表达、低表达与阴性三组，并证实了HER2具备良好的预后意义。 研究发现，HER2高表达组富集DNA修复相关特征，而HER2低表达与阴性组则表现出显著的炎症反应。本研究还观察到，肿瘤突变负荷（tumor mutation burden）或许并非区分这三组患者的核心因素。此外，本研究揭示HER2低表达与阴性组存在肿瘤抑制性免疫微环境。 本研究结果显示，靶向CD47/SIRPA轴的抗炎疗法与免疫检查点抑制（immune checkpoint inhibition）策略，或可作为HER2阴性GCA患者的潜在治疗方案。上述研究发现为胃贲门腺癌的个性化治疗指明了颇具前景的方向。