Xu Yu-Jie, He Min-Ke, Liu Shuang, Huang Li-Chang, Bu Xiao-Yun, Kan Anna, Shi Ming
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Department of Hepatic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
Cancer Cell Int. 2021 Nov 18;21(1):610. doi: 10.1186/s12935-021-02321-z.
The accumulation of single nucleotide variants (SNVs) and the emergence of neoantigens can affect tumour proliferation and the immune microenvironment. However, the SNV-related immune microenvironment characteristics and key genes involved in hepatocellular carcinoma (HCC) are still unclear. We aimed to evaluate differences in the SNV-related immune microenvironment, construct a prognostic model and validate the key genes in vitro.
The categories of samples were defined by the expression of SNV score-related genes to evaluate the differences in mutational features, immune environment and prognosis. The survival model was constructed with survival-associated genes and verified in two independent test datasets. RCAN2, the key gene screened out for biofunction, was validated in vitro.
IC2, among the three integrated clusters (IC1, IC2, IC3) classified by the 82 SNV score-related genes, was distinct from the rest in SNV score and immune cell infiltration, showing a better prognosis. Seven prognostic markers, HTRA3, GGT5, RCAN2, LGALS3, CXCL1, CLEC3B, and CTHRC1, were screened to construct a prognostic model. The survival model distinguished high-risk patients with poor prognoses in three independent datasets (log-rank P < 0.0001, 0.011, and 0.0068, respectively) with acceptable sensitivity and specificity. RCAN2 was inversely correlated with NK cell infiltration, and knockdown of RCAN2 promoted proliferation in HCC.
This study revealed the characteristics of the HCC SNV-associated subgroup and screened seven latent markers for their accuracy of prognosis. Additionally, RCAN2 was preliminarily proven to influence proliferation in HCC and it had a close relationship with NK cell infiltration in vitro. With the capability to predict HCC outcomes, the model constructed with seven key differentially expressed genes offers new insights into individual therapy.
单核苷酸变异（SNV）的积累和新抗原的出现会影响肿瘤增殖和免疫微环境。然而，肝细胞癌（HCC）中与SNV相关的免疫微环境特征及关键基因仍不清楚。我们旨在评估与SNV相关的免疫微环境差异，构建预后模型并在体外验证关键基因。
通过SNV评分相关基因的表达来定义样本类别，以评估突变特征、免疫环境和预后的差异。用生存相关基因构建生存模型，并在两个独立的测试数据集中进行验证。对筛选出的具有生物功能的关键基因RCAN2进行体外验证。
在由82个SNV评分相关基因分类的三个整合簇（IC1、IC2、IC3）中，IC2在SNV评分和免疫细胞浸润方面与其他簇不同，预后较好。筛选出七个预后标志物HTRA3、GGT5、RCAN2、LGALS3、CXCL1、CLEC3B和CTHRC1来构建预后模型。该生存模型在三个独立数据集中区分出预后不良的高危患者（对数秩检验P值分别为<0.0001、0.011和0.0068），且具有可接受的敏感性和特异性。RCAN2与自然杀伤（NK）细胞浸润呈负相关，敲低RCAN2可促进肝癌细胞增殖。
本研究揭示了HCC中与SNV相关亚组的特征，并筛选出七个具有预后准确性的潜在标志物。此外，初步证明RCAN2影响肝癌细胞增殖，且在体外与NK细胞浸润密切相关。用七个关键差异表达基因构建的模型具有预测HCC预后的能力，为个体化治疗提供了新的见解。
