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摘要: 弥漫型胃癌（diffuse gastric cancer，DGC）是一种分化程度低、恶性程度高、临床预后差的胃腺癌亚型，异质性强，可由CDH1基因突变、RHOA基因突变和CLDN18-ARHGAP基因融合等驱动，也存在广泛的环境-基因突变互作，发病机制尚不清楚。已有的DGC研究模型包括基因修饰小鼠、人源肿瘤异种移植（patient-derived tumor xenograft，PDX）模型以及类器官模型，有机整合这些研究模型有助于更加准确地探索DCG病理生理过程，揭示DGC发生机制。临床上尚缺乏高效的DGC治疗药物，近年来开发了MET抑制剂、ROS1抑制剂等多种分子靶向药物，但未获得显著的临床疗效。鉴于此，本文展望宏基因组学、蛋白组学、代谢组学等新兴领域，综合DGC时空异质性、胃癌微生态调控和多组学整合的分子分型等前沿成果，提出DGC精准治疗的未来着力点和攻关方向，以期为DGC精准诊疗提供理论参考。Abstract: Diffuse gastric cancer (DGC) is a subtype of gastric adenocarcinoma with low differentiation, high malignancy, and a poor clinical prognosis. DGC is highly heterogeneous and can be driven by mutations in the CDH1, RHOA, and CLDN18-ARHGAP gene fusion and wide-ranging environmental gene mutation interactions. However, its pathogenesis is unclear. The existing DGC models include transgenic mice, patient-derived tumor xenograft (PDX), and organoid models. The organic integration of these models will aid in a more accurate investigation of the pathophysiological process and the mechanism of DCG. In clinical practice, there is a lack of effective drugs for DGC treatment. Although a few molecular-targeted drugs, such as MET and ROS1 inhibitors, have been developed recently, they have not demonstrated any significant clinical efficacy. Thus, in this paper, we look forward to emerging fields such as metagenomics, proteomics, and metabolomics, and explore cutting-edge perspectives such as spatiotemporal heterogeneity of DGC, gastric cancer microecological regulation, and molecular typing for multi-omics integration, to put forward the focus and direction of DGC precision therapy in future, which can provide theoretical reference for DGC precision diagnosis and treatment.
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Key words:
- diffuse gastric cancer (DGC) /
- molecular subtypes /
- precision medicine
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表 1 DGC小鼠模型
模型 突变基因 病理 Ubiquitous CDH1f/+ cancer-free（8 mo) CDH1f/++MNU intramucosal SRCCs Mist1-Cre Cdh1 f/f atypical foci Cdh1 f/f +H. feils DGC Cdh1 f/f；TP53 LSL-R172H + advanced DGC H. feils Cdh1 f/f cancer-free（14 mo） Mist1- Cre RHOALSL-Y42C/+ cancer-free（14 mo） Cdh1 f/f；RHOA LSL-Y42C/+ advanced DGC Tff1-Cre Cdh1 f/f atypical foci Atp4b-Cre CDH1f/f pre-cancerous lesions CDH1 f/f pre-cancerous lesions CDH1 f/f；Trp53 f/f advanced DGC Anxa10-Cre Cdh1 f/f；Kras LSL-G12D；Smad4 f/f advanced DGC 
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表 2 弥漫型胃癌分子分型
分型 分子亚型 特征 临床预后 治疗策略 转录组分型 INT 肿瘤突变负荷较高；细胞周期及DNA修复相关 较好 免疫治疗 COD 肿瘤突变负荷较高；上皮间质转化相关 较差 化疗 蛋白组分型 PX1 细胞周期相关 较好 较难预测 PX2 细胞周期及上皮间质转化相关 中等 较难预测 PX3 免疫应答较好 较差 免疫治疗及化疗 磷酸蛋白组分型 Ph1 RNA聚合酶Ⅱ转录过程相关 较好 靶向治疗 Ph1 DNA代谢与DNA修复相关 较差 靶向治疗 Ph1 染色体分离过程相关 较差 靶向治疗
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