An Integrating Immune-Related Signature to Improve Prognosis of Hepatocellular Carcinoma

Growing evidence suggests that the superiority of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) could act as biomarkers for cancer prognosis. However, the prognostic marker for hepatocellular carcinoma with high accuracy and sensitivity is still lacking. In this research, a retrospective, cohort-based study of genome-wide RNA-seq data of patients with hepatocellular carcinoma was carried out, and two protein-coding genes (GTPBP4, TREM-1) and one lncRNA (LINC00426) were sorted out to construct an integrative signature to predict the prognosis of patients. The results show that both the AUC and the C-index of this model perform well in TCGA validation dataset, cross-platform GEO validation dataset, and different subsets divided by gender, stage, and grade. The expression pattern and functional analysis show that all three genes contained in the model are associated with immune infiltration, cell proliferation, invasion, and metastasis, providing further confirmation of this model. In summary, the proposed model can effectively distinguish the high- and low-risk groups of hepatocellular carcinoma patients and is expected to shed light on the treatment of hepatocellular carcinoma and greatly improve the patients' prognosis.

[1]  S. Love,et al.  Survival Analysis Part II: Multivariate data analysis – an introduction to concepts and methods , 2003, British Journal of Cancer.

[2]  R. Bataller,et al.  Hepatocarcinoma cells stimulate the growth, migration and expression of pro‐angiogenic genes in human hepatic stellate cells , 2010, Liver international : official journal of the International Association for the Study of the Liver.

[3]  A. Dennison,et al.  Prognostic molecular markers in hepatocellular carcinoma: a systematic review. , 2007, European journal of cancer.

[4]  M. Pellegrini,et al.  Molecular Profiling of Premalignant Lesions in Lung Squamous Cell Carcinomas Identifies Mechanisms Involved in Stepwise Carcinogenesis , 2014, Cancer Prevention Research.

[5]  Jian Zhang,et al.  Cancer Specific Long Noncoding RNAs Show Differential Expression Patterns and Competing Endogenous RNA Potential in Hepatocellular Carcinoma , 2015, PloS one.

[6]  Hong Chen,et al.  RASAL1 influences the proliferation and invasion of gastric cancer cells by regulating the RAS/ERK signaling pathway , 2014, Human Cell.

[7]  W. Lau,et al.  A Prospective Randomized Trial Comparing Percutaneous Local Ablative Therapy and Partial Hepatectomy for Small Hepatocellular Carcinoma , 2006, Annals of surgery.

[8]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[9]  Hsuan-Yu Chen,et al.  TREM-1 expression in tumor-associated macrophages and clinical outcome in lung cancer. , 2008, American journal of respiratory and critical care medicine.

[10]  W. Shi,et al.  Upregulated HOXC8 Expression Is Associated with Poor Prognosis and Oxaliplatin Resistance in Hepatocellular Carcinoma , 2015, Digestive Diseases and Sciences.

[11]  Sandrine Dudoit,et al.  Evaluation of statistical methods for normalization and differential expression in mRNA-Seq experiments , 2010, BMC Bioinformatics.

[12]  L. Qin,et al.  The prognostic molecular markers in hepatocellular carcinoma. , 2002, World journal of gastroenterology.

[13]  Liliana Florea,et al.  Transcriptomic landscape of breast cancers through mRNA sequencing , 2012, Scientific Reports.

[14]  Yang Wang,et al.  Efficacy of Percutaneous Thermal Ablation Combined With Transarterial Embolization for Recurrent Hepatocellular Carcinoma After Hepatectomy and a Prognostic Nomogram to Predict Survival , 2018, Technology in cancer research & treatment.

[15]  Development and Validation of a Three-gene Prognostic Signature for Patients with Hepatocellular Carcinoma , 2017, Scientific Reports.

[16]  Pieter Wesseling,et al.  RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics , 2015, Cancer cell.

[17]  M. Kudo,et al.  Percutaneous Radiofrequency Ablation for Intermediate-Stage Hepatocellular Carcinoma , 2015, Oncology.

[18]  Ariel Linden Measuring diagnostic and predictive accuracy in disease management: an introduction to receiver operating characteristic (ROC) analysis. , 2006, Journal of evaluation in clinical practice.

[19]  Rebecca M. Dodson,et al.  Resection and transplantation for hepatocellular carcinoma: factors influencing surgical options. , 2014, Future oncology.

[20]  S W Lagakos,et al.  Nonparametric estimation of lifetime and disease onset distributions from incomplete observations. , 1982, Biometrics.

[21]  Leili Shahriyari,et al.  Effect of normalization methods on the performance of supervised learning algorithms applied to HTSeq-FPKM-UQ data sets: 7SK RNA expression as a predictor of survival in patients with colon adenocarcinoma , 2019, Briefings Bioinform..

[22]  N. Mantel Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[23]  M. Parsons,et al.  A novel nucleolar G-protein conserved in eukaryotes. , 2001, Journal of cell science.

[24]  Robin K Kelley,et al.  A review of hepatocellular carcinoma (HCC) staging systems. , 2013, Chinese clinical oncology.

[25]  S. J. Henley,et al.  Changing Hepatocellular Carcinoma Incidence and Liver Cancer Mortality Rates in the United States , 2014, The American Journal of Gastroenterology.

[26]  J. Llovet,et al.  New Strategies in Hepatocellular Carcinoma: Genomic Prognostic Markers , 2010, Clinical Cancer Research.

[27]  Eleanor Howe,et al.  RNA-Seq analysis in MeV , 2011, Bioinform..

[28]  Congcong Yan,et al.  Computational recognition of lncRNA signature of tumor-infiltrating B lymphocytes with potential implications in prognosis and immunotherapy of bladder cancer , 2020, Briefings Bioinform..

[29]  M. García-Fiñana,et al.  Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection. , 2018, Journal of hepatology.

[30]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[31]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[32]  Wei Chen,et al.  Design powerful predictor for mRNA subcellular location prediction in Homo sapiens , 2020, Briefings Bioinform..

[33]  Sang Yeon Cho,et al.  Gene expression of NOX family members and their clinical significance in hepatocellular carcinoma , 2017, Scientific Reports.

[34]  Y. Fong,et al.  Hepatocellular carcinoma: current surgical management. , 2001, Seminars in oncology.

[35]  Jiagui Chen,et al.  NEK2 serves as a prognostic biomarker for hepatocellular carcinoma , 2017, International journal of oncology.

[36]  Yi-jun Shen,et al.  Downregulation of DAB2IP results in cell proliferation and invasion and contributes to unfavorable outcomes in bladder cancer , 2014, Cancer science.

[37]  J. Leek svaseq: removing batch effects and other unwanted noise from sequencing data , 2014, bioRxiv.

[38]  Congcong Yan,et al.  Computational principles and practice for decoding immune contexture in the tumor microenvironment , 2020, Briefings Bioinform..

[39]  Jianzhong Su,et al.  Analysis of long noncoding RNAs highlights region-specific altered expression patterns and diagnostic roles in Alzheimer's disease , 2019, Briefings Bioinform..

[40]  Nuno A. Fonseca,et al.  Expression Atlas: gene and protein expression across multiple studies and organisms , 2017, Nucleic Acids Res..

[41]  Fuchu He,et al.  Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers , 2010, Nature Genetics.

[42]  Fernando Pons,et al.  Staging systems in hepatocellular carcinoma. , 2005, HPB : the official journal of the International Hepato Pancreato Biliary Association.

[43]  M. Colonna,et al.  Cutting Edge: Inflammatory Responses Can Be Triggered by TREM-1, a Novel Receptor Expressed on Neutrophils and Monocytes1 , 2000, The Journal of Immunology.

[44]  Dong Wang,et al.  iLoc‐lncRNA: predict the subcellular location of lncRNAs by incorporating octamer composition into general PseKNC , 2018, Bioinform..

[45]  B. Mínguez,et al.  Diagnostic and Prognostic Molecular Markers in Hepatocellular Carcinoma , 2011, Disease markers.

[46]  E. Pomfret,et al.  Surgical resection and liver transplantation for hepatocellular carcinoma. , 2015, Clinics in liver disease.

[47]  Li Liu,et al.  Up-regulation of LncRNA SNHG20 Predicts Poor Prognosis in Hepatocellular Carcinoma , 2016, Journal of Cancer.

[48]  A. Stray-Pedersen,et al.  A newly recognized 13q12.3 microdeletion syndrome characterized by intellectual disability, microcephaly, and eczema/atopic dermatitis encompassing the HMGB1 and KATNAL1 genes , 2014, American journal of medical genetics. Part A.

[49]  Luo Xiaohe,et al.  Several microRNAs could predict survival in patients with hepatitis B-related liver cancer , 2017, Scientific Reports.

[50]  K. Tomczak,et al.  The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge , 2015, Contemporary oncology.

[51]  S. Thorgeirsson,et al.  A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy , 2016, Molecular Pharmacology.

[52]  Zicheng Zhang,et al.  Computational identification of mutator-derived lncRNA signatures of genome instability for improving the clinical outcome of cancers: a case study in breast cancer , 2020, Briefings Bioinform..

[53]  Jiu-Xin Tan,et al.  Early Diagnosis of Hepatocellular Carcinoma Using Machine Learning Method , 2020, Frontiers in Bioengineering and Biotechnology.

[54]  G. Chen,et al.  A Seven-microRNA Expression Signature Predicts Survival in Hepatocellular Carcinoma , 2015, PloS one.

[55]  S. Qiu,et al.  Expression of TREM‐1 in hepatic stellate cells and prognostic value in hepatitis B‐related hepatocellular carcinoma , 2012, Cancer science.

[56]  S. Qiu,et al.  Quantitative assessment of the effect of glutathione S-transferase genes GSTM1 and GSTT1 on hepatocellular carcinoma risk , 2014, Tumor Biology.

[57]  Yan Huang,et al.  RNALocate: a resource for RNA subcellular localizations , 2016, Nucleic Acids Res..

[58]  Congcong Yan,et al.  Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer , 2020, Journal for ImmunoTherapy of Cancer.

[59]  S. Fan,et al.  Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. , 2014, Gastroenterology.

[60]  Zhiyong Liang,et al.  Expression of GRK2 and IGF1R in hepatocellular carcinoma: clinicopathological and prognostic significance , 2017, Journal of Clinical Pathology.

[61]  B. Taylor,et al.  Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. , 2014, Cancer research.

[62]  London Wt,et al.  Can Propranalol Prevent Hepatocellular Carcinoma , 2012 .

[63]  Kuen-Feng Chen,et al.  Treatment of Liver Cancer. , 2015, Cold Spring Harbor perspectives in medicine.

[64]  Jianzhong Su,et al.  Recurrence-Associated Long Non-coding RNA Signature for Determining the Risk of Recurrence in Patients with Colon Cancer , 2018, Molecular therapy. Nucleic acids.

[65]  W. Niu,et al.  A three-long non-coding RNA-expression-based risk score system can better predict both overall and recurrence-free survival in patients with small hepatocellular carcinoma , 2018, Aging.

[66]  K. McGlynn,et al.  Can Propranalol Prevent Hepatocellular Carcinoma? , 2012, Cancer Prevention Research.

[67]  Seung‐Mo Hong,et al.  Multiplexed gene expression profiling identifies the FGFR4 pathway as a novel biomarker in intrahepatic cholangiocarcinoma , 2017, Oncotarget.