鉴定与染色质组织相关的基因特征，用于预测肝细胞癌的预后和免疫治疗反应。

Identification of chromatin organization-related gene signature for hepatocellular carcinoma prognosis and predicting immunotherapy response.

机构信息

Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.

Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.

出版信息

Int Immunopharmacol. 2022 Aug;109:108866. doi: 10.1016/j.intimp.2022.108866. Epub 2022 Jun 9.

DOI:10.1016/j.intimp.2022.108866

PMID:35691273

Abstract

BACKGROUND

Chromatin organization is associated with tumorigenesis; however, information on its role in hepatocellular carcinoma (HCC) is limited. Moreover, although immune checkpoint inhibitors (ICIs) have proven effective against HCC, the optimal index remains unknown. In this study, we aimed to construct a chromatin organization-related gene signature (CORGS) for prognosis and predicting response to ICIs in HCC.

METHODS

HCC-related data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Construction (ICGC). Chromatin organization-related genes (CORGs) were retrieved from Gene Set Enrichment Analysis. Differentially expressed genes (DEGs) and prognostic genes were then applied to select candidate genes using advanced statistical methods, including learning vector quantization, random forest, and lasso regression. Subsequently, the CORGS was established based on chromatin organization-related hub genes using multivariate Cox regression analysis, evaluated with Kaplan-Meier survival curves, and verified in 64 samples of HCC patients from Fujian Provincial Hospital (FPH) via quantitative PCR. Subsequently, functional enrichment analysis, tumor somatic mutation analysis, and tumor immune analysis were performed to evaluate the potential value of the CORGS.

RESULTS

Three hundred and thirty-nine CORGs were identified as DEGs, and 186 were associated with HCC prognosis (all P < 0.05). Four intersection genes were selected to establish the CORGS using TCGA cohort, which was found to serve as an independent risk factor for HCC patients. CORGS was then validated in an ICGC cohort. In addition, CORGS reliability was verified in 64 samples from HCC patients and 26 adjacent non-tumorous tissues, collected from the FPH. The CORGS was also associated with tumor immune microenvironment characteristics and ICI response. Moreover, data from "IMvigor 210" revealed that more patients in the low CORGS group responded to atezolizumab compared to high CORGS patients (P < 0.05). Finally, a nomogram of tumor characteristics and the CORGS was established, exhibiting superior discrimination and calibration compared to the current staging system and published models.

CONCLUSIONS

CORGS may serve as an effective predictive biomarker for HCC as well as a potential index of the tumor immune microenvironment and ICI response.

摘要

背景

染色质组织与肿瘤发生有关；然而，其在肝细胞癌（HCC）中的作用信息有限。此外，尽管免疫检查点抑制剂（ICIs）已被证明对 HCC 有效，但最佳指标仍不清楚。在这项研究中，我们旨在构建一个与染色质组织相关的基因特征（CORGS），用于预测 HCC 的预后和对 ICI 的反应。

方法

从癌症基因组图谱（TCGA）和国际癌症基因组联盟（ICGC）中获取 HCC 相关数据。从基因集富集分析中检索与染色质组织相关的基因（CORGs）。然后应用先进的统计方法（包括学习向量量化、随机森林和套索回归）从差异表达基因（DEGs）和预后基因中选择候选基因。随后，基于与染色质组织相关的枢纽基因，使用多变量 Cox 回归分析建立 CORGS，通过 Kaplan-Meier 生存曲线进行评估，并通过来自福建省立医院（FPH）的 64 例 HCC 患者的定量 PCR 进行验证。随后进行功能富集分析、肿瘤体细胞突变分析和肿瘤免疫分析，以评估 CORGS 的潜在价值。

结果

确定了 339 个与 HCC 相关的 DEGs，其中 186 个与 HCC 的预后相关（均 P < 0.05）。使用 TCGA 队列选择 4 个交叉基因来建立 CORGS，发现该基因可作为 HCC 患者的独立危险因素。然后在 ICGC 队列中验证了 CORGS。此外，在来自 FPH 的 64 例 HCC 患者和 26 例相邻非肿瘤组织的样本中验证了 CORGS 的可靠性。CORGS 还与肿瘤免疫微环境特征和 ICI 反应相关。此外，来自“IMvigor 210”的数据表明，低 CORGS 组的患者对阿特珠单抗的反应率高于高 CORGS 患者（P < 0.05）。最后，建立了一个包含肿瘤特征和 CORGS 的列线图，与当前的分期系统和已发表的模型相比，具有更好的区分度和校准度。