Wang Xu, Xu Bing, Du Jing, Xia Jun, Lei Guojie, Zhou Chaoting, Hu Jiayu, Zhang Yinhao, Chen Sufeng, Shao Fangchun, Yang Jiyun, Li Yanchun
Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, 610072, Sichuan, China.
Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China.
Cancer Cell Int. 2022 Oct 13;22(1):317. doi: 10.1186/s12935-022-02739-z.
Gastric cancer is one of the most common malignancies of the digestive system with a high lethal rate. Studies have shown that inherited and acquired mutations in pyruvate metabolism and citric acid cycle (P-CA) enzymes are involved in tumorigenesis and tumor development. However, it is unclear how different P-CA patterns affect the tumor microenvironment (TME), which is critical for cancer progression.
This study mainly concentrated on investigating the role of the P-CA patterns in multicellular immune cell infiltration of GC TME. First, the expression levels of P-CA regulators were profiled in GC samples from The Cancer Genome Atlas and Gene Expression Omnibus cohorts to construct a consensus clustering analysis and identify three distinct P-CA clusters. GSVA was conducted to reveal the different biological processes in three P-CA clusters. Subsequently, 1127 cluster-related differentially expressed genes were identified, and prognostic-related genes were screened using univariate Cox regression analysis. A scoring system was then set up to quantify the P-CA gene signature and further evaluate the response of the patients to the immunotherapy.
We found that GC patients in the high P-CA score group had a higher tumor mutational burden, higher microsatellite instability, and better prognosis. The opposite was observed in the low P-CA score group. Interestingly, we demonstrated P-CA gene cluster could predict the sensitivity to immunotherapy and ferroptosis-induced therapy.
Collectively, the P-CA gene signature in this study exhibits potential roles in the tumor microenvironment and predicts the response to immunotherapeutic. The identification of these P-CA patterns may significantly accelerate the strategic development of immunotherapy for GC.
胃癌是消化系统最常见的恶性肿瘤之一，致死率高。研究表明，丙酮酸代谢和柠檬酸循环（P-CA）酶的遗传和获得性突变参与肿瘤发生和肿瘤发展。然而，尚不清楚不同的P-CA模式如何影响肿瘤微环境（TME），而肿瘤微环境对癌症进展至关重要。
本研究主要集中于调查P-CA模式在胃癌TME多细胞免疫细胞浸润中的作用。首先，在来自癌症基因组图谱和基因表达综合数据库队列的胃癌样本中分析P-CA调节因子的表达水平，以构建共识聚类分析并识别三种不同的P-CA簇。进行基因集变异分析（GSVA）以揭示三个P-CA簇中的不同生物学过程。随后，鉴定了1127个与簇相关的差异表达基因，并使用单变量Cox回归分析筛选了与预后相关的基因。然后建立一个评分系统来量化P-CA基因特征，并进一步评估患者对免疫治疗的反应。
我们发现高P-CA评分组的胃癌患者具有更高的肿瘤突变负荷、更高的微卫星不稳定性和更好的预后。在低P-CA评分组中观察到相反的情况。有趣的是，我们证明P-CA基因簇可以预测对免疫治疗和铁死亡诱导治疗的敏感性。
总体而言，本研究中的P-CA基因特征在肿瘤微环境中发挥潜在作用，并预测对免疫治疗的反应。这些P-CA模式的鉴定可能会显著加速胃癌免疫治疗的战略发展。
