Xu Rongji, He Danni, Sun Rui, Zhou Jiaqi, Xin Mengyu, Liu Qian, Dai Yifan, Li Houxing, Zhang Yujie, Li Jiatong, Shan XinXin, He Yuting, Xu Borui, Guo Qiuyan, Ning Shangwei, Gao Yue, Wang Peng
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
The First Clinical School of Gansu University of Chinese Medicine, Lanzhou, 730030, China.
J Transl Med. 2025 Mar 11;23(1):308. doi: 10.1186/s12967-025-06222-x.
Gastric cancer (GC) is a highly heterogeneous tumour with high morbidity. Approximately 95% of GC cases are gastric adenocarcinomas, which are further categorized into two predominant subtypes: diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC). These subtypes exhibit distinct pathophysiological and molecular characteristics, reflecting their unique tumorigenic mechanisms.
In this study, we employed a comprehensive approach to identify driver genes associated with DGC and IGC by focusing on copy number variation (CNV) genes within the competing endogenous RNA (ceRNA) network. The influence of driver CNV genes on the molecular, cellular, and clinical differences between DGC and IGC was subsequently analysed. Finally, therapeutic strategies for DGC and IGC were evaluated based on the status and functional pathways of the driver CNV genes.
A total of 17 and 22 driver CNV genes were identified in DGC and IGC, respectively. These genes drive subtype differences through the ceRNA network, resulting in alterations in the tumour microenvironment (TME). Based on these differences, personalized treatment strategies for DGC or IGC could be developed. Immune checkpoint inhibitors may be an effective treatment option in IGC. Additionally, DGC patients with homozygous deletion of PPIF might benefit from adjuvant chemotherapy, whereas those with high-level amplification of MTAP could respond to targeted therapy.
Driver CNV genes were identified to reveal the underlying cause of heterogeneity in DGC and IGC. Furthermore, specific driver CNV genes were identified as potential therapeutic targets, facilitating personalized treatment.
胃癌（GC）是一种发病率高且高度异质性的肿瘤。约95%的GC病例为胃腺癌，其进一步分为两种主要亚型：弥漫性胃癌（DGC）和肠型胃癌（IGC）。这些亚型表现出不同的病理生理和分子特征，反映了它们独特的致瘤机制。
在本研究中，我们采用综合方法，通过关注竞争性内源RNA（ceRNA）网络中的拷贝数变异（CNV）基因来鉴定与DGC和IGC相关的驱动基因。随后分析了驱动CNV基因对DGC和IGC之间分子、细胞和临床差异的影响。最后，根据驱动CNV基因的状态和功能途径评估了DGC和IGC的治疗策略。
在DGC和IGC中分别鉴定出17个和22个驱动CNV基因。这些基因通过ceRNA网络驱动亚型差异，导致肿瘤微环境（TME）发生改变。基于这些差异，可以制定DGC或IGC的个性化治疗策略。免疫检查点抑制剂可能是IGC的一种有效治疗选择。此外，PPIF纯合缺失的DGC患者可能从辅助化疗中获益，而MTAP高水平扩增的患者可能对靶向治疗有反应。
鉴定出驱动CNV基因以揭示DGC和IGC异质性的潜在原因。此外，特定的驱动CNV基因被确定为潜在的治疗靶点，有助于个性化治疗。
