Mining immune-related genes with prognostic value in the tumor microenvironment of breast invasive ductal carcinoma

The tumor microenvironment (TME) plays an important role in the development of breast cancer. Due to limitations in experimental conditions, the molecular mechanism of TME in breast cancer has not yet been elucidated. With the development of bioinformatics, the study of TME has become convenient and reliable.Gene expression and clinical feature data were downloaded from The Cancer Genome Atlas database and the Molecular Taxonomy of Breast Cancer International Consortium database. Immune scores and stromal scores were calculated using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data algorithm. The interaction of genes was examined with protein-protein interaction and co-expression analysis. The function of genes was analyzed by gene ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes analysis and gene set enrichment analysis. The clinical significance of genes was assessed with Kaplan-Meier analysis and univariate/multivariate Cox regression analysis.Our results showed that the immune scores and stromal scores of breast invasive ductal carcinoma (IDC) were significantly lower than those of invasive lobular carcinoma. The immune scores were significantly related to overall survival of breast IDC patients and both the immune and stromal scores were significantly related to clinical features of these patients. According to the level of immune/stromal scores, 179 common differentially expressed genes and 5 hub genes with prognostic value were identified. In addition, the clinical significance of the hub genes was validated with data from the molecular taxonomy of breast cancer international consortium database, and gene set enrichment analysis analysis showed that these hub genes were mainly enriched in signaling pathways of the immune system and breast cancer.We identified five immune-related hub genes with prognostic value in the TME of breast IDC, which may partly determine the prognosis of breast cancer and provide some direction for development of targeted treatments in the future.     

Reliability of a single-region sample to evaluate tumor immune microenvironment in hepatocellular carcinoma

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Study on the gene signature related to immune microenvironment on viral and nonviral infections of hepatocellular carcinoma

The pathogenesis of hepatocellular carcinoma (HCC) can be divided into viral infection (VIR) and nonviral (NVIR) infection. Two types of HCC performed different tumor immune microenvironment (TIME) which directly affected prognosis of HCC. This study aimed to identify an effective 2 types of HCC prognostic gene signature that related to immune TIME.The differential expression genes (DEGs) were analyzed by Limma R package from the Cancer Genome Atlas. Immune related genes getting from IMMport database were matched to DEGs for testing prognosis. Prognostic index (PI) consisted of prognostic immune related genes was calculated in different types of HCC by COX regression and the correlation with the abundance of immune infiltrates, including 6 type cells, via gene modules. Tumor immune estimation resource database was applied to analyze TIME. Finally, the correlations between PI of DEGs and TIICs were analyzed by the Spearman method.Results showed that PI consisted of 11 messenger RNAs in VIR and 12 messenger RNAs in NVIR groups. The PI related to HCC prognosis has different correlations with immune infiltrating cells in VIR and NVIR groups. The PI value of DEGs has significant correlations with neutrophils (R = 0.22, P-value = .029) and dendritic (R = 0.21, P-value = .036) infiltration levels in VIR group. However, in NVIR group, the result showed there were no significant correlations between PI and other 5 type cell infiltration levels (P-value > .05).The 11-gene signature in VIR and 12-gene signature in NVIR group selected based on data from the Cancer Genome Atlas database had a different correlation with immune infiltrating cells of HCC patients.     

肝细胞癌诊治中的若干问题

随着肝细胞癌（HCC）肿瘤标志物和CT／MRI诊断的应用、手术切除及局部消融等治疗方法的进步,使HCC的5年生存率达到了63．4％。但是由于我国HCC早期诊断水平的不均衡,可进行手术切除的病例仅仅有20％～30％。对于高危人群定期开展血清肿瘤标志物和肝脏超声检查;提高三期动态增强CT和Gd—DTPA增强MRI等影像学诊断水平,同时积极开展多学科会诊,制定个性化治疗方案和减少术后肝功能衰竭发生等若干问题,是提高我国HCC早期诊断水平,提高治疗效果,延长生存期的有效手段。     

A novel immune signature to predict the prognosis of patients with hepatocellular carcinoma

Aberrant immunity has been associated with the initiation and progression of cancers such as hepatocellular carcinoma (HCC). Here, we aim to develop a signature based on immune-related genes (IRGs) to predict the prognosis of HCC patients. The gene expression profiles of 891 HCC samples were derived from 4 publicly accessible datasets. A total of 1534 IRGs from Immunology Database and Analysis Portal website were obtained as candidate genes for prognostic assessment. Using least absolute shrinkage and selection operator (LASSO) regression analysis, 12 IRGs were selected as prognostic biomarkers and were then aggregated to generate an IRG score for each HCC sample. In the training dataset (n = 365), patients with high IRG scores showed a remarkably poorer overall survival than those with low IRG scores (log-rank P < .001). Similar results were documented in 3 independent testing datasets (n = 226, 221, 79, respectively). Multivariate Cox regression and stratified analyses indicated that the IRG score was an independent and robust signature to predict the overall survival in HCC patients. Patients with high IRG scores tended to be in advanced TNM stages, with increased risks of tumor recurrence and metastasis. More importantly, the IRG score was strongly associated with certain immune cell counts, gene expression of immune checkpoints, estimated immune score, and mutation of critical genes in HCC. In conclusion, the proposed IRG score can predict the prognosis and reflect the tumor immune microenvironment of HCC patients, which may facilitate the individualized treatment and provide potential immunotherapeutic targets.     

Immune microenvironment of hepatocellular carcinoma,intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.     

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

BACKGROUND: Four tumor markers for hepatocellular carcinoma(HCC), alpha-fetoprotein(AFP), glypican-3(GPC3), vascular endothelial growth factor(VEGF) and des-gammacarboxy prothrombin(DCP), are closely associated with tumor invasion and patient's survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy.METHODS: A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups: patients with macroscopic vascular invasion(Ma VI +) and those without Ma VI(Ma VI-). The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis.RESULTS: In all patients, tumor size(8 cm) and Ma VI were closely related to HCC recurrence after hepatectomy. For Ma VI+ patients, VEGF(900 pg/m L) was a significant predictor for recurrence(RR=2.421; 95% CI: 1.272-4.606; P=0.007). The 1- and 2-year tumor-free survival rates for Ma VI+ patients with VEGF ≤900 pg/m L versus for those with VEGF 900 pg/m L were 51.5% and 17.6% versus 19.0% and 4.8%(P0.001). For Ma VI- patients, DCP 445 m Au/m L and tumor size 8 cm were two independent risk factors for tumor recurrence(RR=2.307, 95% CI: 1.132-4.703, P=0.021; RR=3.150, 95% CI: 1.392-7.127, P=0.006; respectively). The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 m Au/m L and those with DCP 445 m Au/m L were 90.4% and 70.7% versus 73.2% and 50.5% respectively(P=0.048). The 1-and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and 8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively(P=0.003).CONCLUSIONS: The Ma VI+ patients with VEGF ≤900 pg/m L had a relatively high tumor-free survival than those with VEGF 900 pg/m L. In the Ma VI- patients, DCP 445 m Au/m L and tumor size 8 cm were predictive factors for postoperative recurrence.     

同种异基因皮肤移植对昆明小鼠荷H22型肝癌细胞生长的影响

目的观察同种异基因皮肤移植对昆明小鼠肝细胞癌生长及相关免疫指标的影响。方法采用荷H22型肝癌昆明小鼠为动物模型并分为3组,在皮下接种小鼠H22肝癌细胞悬液后,接受C57／BL6小鼠皮肤移植物的昆明小鼠为实验组,而接受同种同基因移植和不移植组均作为对照组,比较肿瘤的生长情况;同时检测小鼠外周血淋巴细胞亚群和肿瘤组织内细胞的凋亡细胞,比较各组间差异。结果接受同种异基因皮肤移植的昆明小鼠,肿瘤的生长速度慢于其他2组;接受同种异基因皮肤移植的小鼠瘤组织内凋亡细胞数量高于对照组。结论同种异基因皮肤移植对小鼠H22肝癌细胞的生长具有抑制作用,这种作用可能通过诱导肝癌细胞凋亡而发挥作用。     

肿瘤相关成纤维细胞在肝细胞癌生长和转移中的作用

肿瘤的发生发展过程与肿瘤微环境密切相关,肿瘤相关成纤维细胞(CAF)是肿瘤微环境中重要组成成分之一,在肿瘤的发生、血管生成、侵袭和转移过程中扮演着十分重要的角色。从CAF的募集、活化、促血管生成及调节肿瘤免疫等方面对CAF在肝细胞癌(HCC)的发生及发展过程中的作用进行综述,为HCC的治疗提供新的思路。     

Absence of association between pretransplant serum soluble programmed death protein-1 level and prognosis following living donor liver transplantation in patients with hepatocellular carcinoma

Programmed death protein 1 (PD-1) pathway is one of the most critical mechanisms in tumor biology of hepatocellular carcinoma (HCC). The study aimed to assess the prognostic influence of pretransplant serum soluble PD-1 (sPD-1) in patients undergoing liver transplantation for treatment of HCC.Data from 229 patients with HCC who underwent living donor liver transplantation between January 2010 and December 2015 were retrospectively evaluated. Stored serum samples were used to measure sPD-1 concentrations.Overall survival (OS) and disease-free survival (DFS) rates were 94.3% and 74.5% at 1 year; 78.2% and 59.2% at 3 years; and 75.4% and 55.5% at 5 years, respectively. Prognostic analysis using pretransplant serum sPD-1 with a cut-off of 93.6 μg/mL (median value of the study cohort) did not have significant prognostic influence on OS (P = .69) and DFS (P = .26). Prognostic analysis using sPD-1 with a cut-off of 300 μg/mL showed similar OS (P = .46) and marginally lower DFS (P = .070). Combination of Milan criteria and sPD-1 with a cutoff of 300 μg/mL showed similar outcomes of OS and DFS in patients within and beyond Milan criteria. Multivariate analysis revealed that only Milan criteria was an independent prognostic for OS and DFS, but pretransplant sPD1 with a cut-off of 300 μg/mL did not become a prognostic factor.The results of this study demonstrate that pretransplant serum sPD-1 did not show significant influences on post-transplant outcomes in patients with HCC. Further large-scale, multicenter studies are necessary to clarify the role of serum sPD-1 in liver transplantation recipients.     

基于TCGA研究细胞坏死相关基因对肝细胞癌患者预后的影响

目的 研究细胞坏死相关基因对肝细胞癌(HCC)患者预后的影响。方法 自癌症基因组图谱TCGA数据库下载HCC患者mRNA水平数据及其对应的临床资料。应用LASSO Cox回归在TCGA文件中构建多坏死相关基因预后模型。结果 在单因素Cox回归分析中,23个细胞坏死相关差异水平基因与预后生存相关(P<0.05);构建一个显著相关的6个细胞坏死相关基因的预后模型,发生高风险组总体生存期显著低于低风险组(P<0.01);多因素Cox回归分析风险评分符合独立的预后因子标准(P<0.O1);对差异水平基因进行富集分析(GO/KEGG)和单样本基因集富集分析(ssGSEA),发现差异基因与免疫通路显著相关(P<0.05)。结论 通过6个细胞坏死相关基因构建的预后模型可以用于预测HCC患者的预后,或许能为HCC患者的临床治疗提供参考。     

肝细胞癌肿瘤标志物的研究进展

肿瘤标志物检测是目前协助诊断、监测肝细胞癌(HCC)及评估预后的重要方法之一。总结了肿瘤标志物对HCC的诊断、预测肿瘤生物学特性及预后等方面的价值,以及多项肿瘤标志物联合诊断的价值。新的肿瘤标志物不断被发现,有助于提高HCC的早期诊断率和评估治疗效果。     

Screening and identification of key genes between liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) by bioinformatic analysis

Background:Liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) are common primary liver cancers worldwide. Liver stem cells have biopotential to differentiate into either hepatocytes and cholangiocytes, the phenotypic overlap between LIHC and CHOL has been acceptable as a continuous liver cancer spectrum. However, few studies directly investigated the underlying molecular mechanisms between LIHC and CHOL.Method:To identify the candidate genes between LIHC and CHOL, three data series including {"type":"entrez-geo","attrs":{"text":"GSE31370","term_id":"31370"}}GSE31370, {"type":"entrez-geo","attrs":{"text":"GSE15765","term_id":"15765"}}GSE15765 and {"type":"entrez-geo","attrs":{"text":"GSE40367","term_id":"40367"}}GSE40367 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape.Results:A total of 171 DEGs were identified, consisting of 49 downregulated genes and 122 upregulated genes. Compared with CHOL, the enriched functions of the DEGs mainly included steroid metabolic process, acute inflammatory response, coagulation. Meanwhile, the pathway of KEGG enrichment analyses showed that the upregulated gene(s) were mainly enriched complement and coagulation cascades, cholesterol metabolism and PPAR signaling pathway, while the downregulated gene(s) were mainly enriched in ECM-receptor interaction, focal adhesion, bile secretion. Similarly, the most significant module was identified and biological process analysis revealed that these genes were mainly enriched in regulation of blood coagulation, acute inflammatory response, complement and coagulation cascades. Finally, two (ITIH2 and APOA2) of 10 hub genes had been screened out to help differential diagnosis.Conclusion:171 DEGs and two (ITIH2 and APOA2) of 10 hub genes identified in the present study help us understand the different molecular mechanisms between LIHC and CHOL, and provide candidate targets for differential diagnosis.     

局部注射肿瘤浸润淋巴细胞治疗肝癌

探索介入化疗、局部注射TIL、瘤内无水酒精注射综合治疗晚期肝癌的疗效。活检肝癌组织(2—3)g，体外分离、培养扩增TIL，在介入化疗的基础上经皮癌灶注射TIL。患者PR时间、带瘤存活时间明显延长，症状明显改善。综合应用介入化疗、局部注射TIL、瘤内无水酒精注射可明显提高晚期肝癌疗效。