Ma Zhao, Li Mengting, Li Fuqiang, Wu Kui, Wu Xianxian, Luo Tian, Gao Na, Luo Huijuan, Sui Zhilin, Yu Zhentao, Jiang Hongjing, Shang Xiaobin, Chen Chuangui, Yue Jie, Meng Fianbiao, Duan Xiaofeng, Xu Bo
Department of Biochemistry and Molecular Biology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Department of Minimally Invasive Esophageal Surgery, Key Laboratory of Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
Gastric Cancer. 2025 May;28(3):344-357. doi: 10.1007/s10120-025-01585-y. Epub 2025 Jan 30.
Gastroesophageal junction adenocarcinoma (GEJAC) exhibits distinct molecular characteristics due to its unique anatomical location. We sought to investigate effective and reliable molecular classification of GEJAC to guide personalized treatment.
We analyzed the whole genomic, transcriptomic, T-cell receptor repertoires, and immunohistochemical data in 92 GEJAC patients and delineated the landscape of genetic and immune alterations. In addition to COSMIC nomenclature, the de novo nomenclature was also utilized to define signatures and investigate their correlation with survival. A novel molecular subtype was developed and validated in other cohorts.
We found 30 mutated driver genes, 7 novel genomic signatures, 3 copy-number variations, and 2 V-J gene usages related to prognosis that were not identified in previous study. A high frequency of COSMIC-SBS-384-1 and De novo-SV-32-A was associated with more neoantigen generation and a better survival. Using 19 molecular features, we identified three immune-related subtypes (immune inflamed, intermediate, and deserted) with discrete profiles of genomic signatures, immune status, and clinical outcome. The immune deserted subtype (27.2%) was characterized by an earlier KRAS mutation, worse immune reaction, and prognosis than the other two subtypes. The immune inflamed subtypes exhibited the highest levels of neoantigens, TCR/pMHC-binding strength, CD8 + T-cell infiltration, IFN-α/γ response pathways, and survival rate.
These results emphasize the immune reaction and prognostic value of novel molecular classifications based on multi-omics data and provide a solid basis for better management of GEJAC.
胃食管交界腺癌（GEJAC）因其独特的解剖位置而具有独特的分子特征。我们试图研究GEJAC有效的、可靠的分子分类，以指导个性化治疗。
我们分析了92例GEJAC患者的全基因组、转录组、T细胞受体库和免疫组化数据，并描绘了基因和免疫改变的全貌。除了COSMIC命名法外，还使用了从头命名法来定义特征并研究它们与生存的相关性。一种新的分子亚型在其他队列中得到开发和验证。
我们发现了30个突变的驱动基因、7个新的基因组特征、3个拷贝数变异以及2种与预后相关的V-J基因用法，这些在以前的研究中均未被发现。高频率的COSMIC-SBS-384-1和De novo-SV-32-A与更多新抗原的产生和更好的生存相关。利用19个分子特征，我们确定了三种免疫相关亚型（免疫炎症型、中间型和荒芜型），它们具有不同的基因组特征、免疫状态和临床结果。免疫荒芜亚型（27.2%）的特征是KRAS突变较早、免疫反应较差且预后比其他两种亚型差。免疫炎症亚型表现出最高水平的新抗原、TCR/pMHC结合强度、CD8+T细胞浸润、IFN-α/γ反应途径和生存率。
这些结果强调了基于多组学数据的新型分子分类的免疫反应和预后价值，并为更好地管理GEJAC提供了坚实的基础。
