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胃癌病理风险评分与患者预后及肿瘤生物学行为的相关性

The correlation between pathological risk score of gastric cancer and patient prognosis as well as tumor biological behavior

    摘要
  • 摘要:
    目的 探讨胃癌病理风险评分（pathological risk score of gastric cancer, PRSGC）对胃癌患者预后的预测作用，并进一步探究PRSGC与肿瘤生物学行为的相关性。
    方法 回顾性收集2006年4月至2019年11月于复旦大学附属中山医院接受手术切除的1 120例胃癌患者的临床病理资料。利用前期构建的DeepRisk模型计算PRSGC，并按中位PRSGC值将患者分为高、低PRSGC组（各560例），检测两组患者胃癌组织中免疫细胞亚群比例及空间距离。整合癌症基因组图谱中胃腺癌样本数据，分析与PRSGC相关的基因突变及信号通路。
    结果 高PRSGC组的生存率低于低PRSGC组，复发率高于低PRSGC组（P＜0.000 1）。高PRSGC组肿瘤区域内较正常区域的调节性T细胞（regulatory T cell, Treg）和中性粒细胞浸润密度增加（P＜0.05），而自然杀伤性T细胞和细胞毒性T细胞浸润密度下降（P＜0.05）。空间分析显示，CD4+ T细胞与Treg的空间距离缩短与高PRSGC组患者的不良预后相关（P＝0.03）。此外，高PRSGC组肿瘤微环境内TIM3+细胞数量与Treg细胞（r＝0.69，P＝0.01）、CD8+ T细胞（r＝0.61，P＝0.04）、CD4+ T细胞（r＝0.67，P＝0.02）浸润水平均正相关。基因富集分析显示，高PRSGC与肌动蛋白细胞骨架调控、cGMP-PKG通路、Hippo通路和肿瘤蛋白聚糖通路激活相关。
    结论 高PRSGC与肿瘤免疫抑制微环境及肿瘤侵袭、转移相关，能有效预测胃癌患者预后，并为个体化靶向联合免疫治疗策略的制定提供潜在理论依据。

     

    Abstract:
    Objective To explore the predictive role of pathological risk score of gastric cancer (PRSGC) in the prognosis of gastric cancer patients, and to further investigate the correlation between PRSGC and tumor biological behavior.
    Methods Clinicopathological data were retrospectively collected from 1 120 patients with gastric cancer who underwent surgical resection at Zhongshan Hospital, Fudan University, between April 2006 and November 2019. PRSGC was calculated using the previously established DeepRisk model, and patients were divided into high and low PRSGC groups (560 patients per group) based on the median PRSGC value. The proportions and spatial distances of immune cell subsets in gastric cancer tissues were assessed between the two groups. Data from stomach adenocarcinoma samples in The Cancer Genome Atlas was integrated to analyze PRSGC-associated genetic mutations and signaling pathways.
    Results The survival rate of the high PRSGC group was lower than that of the low PRSGC group, and the recurrence rate was higher than that of the low PRSGC group (P<0.000 1). Compared with the low-PRSGC group, the high-PRSGC group exhibited increased infiltration of regulatory T cells (Tregs) and neutrophils within the tumor region (P＜0.05), while the infiltration levels of natural killer T cells and cytotoxic T cells were markedly decreased (P＜0.05). Spatial analysis revealed that a shortened spatial distance between CD4+ T cells and Tregs was closely associated with poor prognosis in the high-PRSGC group (P＝0.03). Furthermore, in the high-PRSGC group, the number of TIM3+ cells showed a positive correlation with the infiltration levels of Tregs (r＝0.69, P＝0.01), CD8+ T cells (r＝0.61, P＝0.04), and CD4+ T cells (r＝0.67, P＝0.02). Gene set enrichment analysis indicated that a high PRSGC was associated with the activation of pathways related to actin cytoskeleton regulation, the cGMP-PKG pathway, the Hippo pathway, and tumor proteoglycans.
    Conclusion A high PRSGC is associated with an immunosuppressive tumor microenvironment, as well as tumor invasion and metastasis. It effectively predicts the prognosis of patients with gastric cancer and, by doing so, provides a potential theoretical basis for developing individualized strategies that combine targeted therapy with immunotherapy.

     

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