Classification and survival prediction in early‐stage cirrhosis by gene expression profiling

Abstract

Liver cirrhosis has been increasingly diagnosed at an early stage owing to the noninvasive diagnostic techniques. However, it is difficult to identify patients at high risk of disease progression. Screening cirrhotic patients with poor prognosis who are most in need of surveillance is still challenging. Gene expression data GSE15654 and GSE14520 were downloaded for performing unsupervised clustering analysis. The prognostic differences between the different clusters were explored by Cox regression. Integrative analysis of gene expression signature, immune cell enrichments and clinical characterization was performed for different clusters. Two distinctive subclasses were identified in HCV-related GSE15654, and Kaplan-Meier analysis indicated that subtype 2 had lower survival rates than subtype 1 (p = 0.0399). Further analysis revealed subtype 2 had a higher density of follicular T helper cells, resting natural killer cells and M0, M2 macrophages while subtype 1 with a higher fraction of naive B cells, memory B cells, resting memory CD 4 T cells, activated natural killer cells and monocytes. 226 differentially expressed genes were identified between the two subtypes, and Reactome analysis showed the mainly enriched pathways were biological oxidations and fatty acid metabolism. Five hub genes (AKT1, RPS16, CDC42, CCND1 and PCBP2) and three significant modules were extracted from the PPI network. The results were validated in HBV-related GSE14520 cohort. We identified two subtypes of patients with different prognosis for hepatitis C-related early-stage liver cirrhosis. Bioinformatics analysis of the gene expression and immune cell profile may provide fresh insight into understanding the prognosis difference. K E Y W O R D Simmune cells, liver cirrhosis, microarray analysis, prognosis, unsupervised clustering | INTRODUC TI ONCirrhosis results from many forms of chronic liver damage and hepatitis C virus (HCV) infection is one of the major aetiologies. 1 HCV-related cirrhosis is a common and growing public health problem globally. 2 The wide use of non-invasive diagnostic techniques promises to increase the number of newly identified patients with early-stage liver cirrhosis. 3 Clinical management of this growing patient population poses challenges for current medical resources. Despite a sustained virologic response being achieved after antiviral therapy, HCV eradication is not generally sufficient to eliminate the risk of the cirrhosis complications. 4 The mortality is mainly