Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma.

Zijing Lin,Guochao Zhong,Jianping Gong,Lei Zhao,Zhibo Zhao,Dong Cai,Jiejun Hu

doi:10.3389/fonc.2021.666847

Abstract

BackgroundCholangiocarcinoma is an aggressive carcinoma with increasing incidence and poor outcomes worldwide. Genomic instability and alternative splicing (AS) events are hallmarks of carcinoma development and progression. The relationship between genomic instability, AS events, and tumor immune microenvironment remain unclear.MethodsThe splicing profiles of patients with cholangiocarcinoma were obtained from The Cancer Genome Atlas (TCGA) spliceSeq database. The transcriptomics, simple nucleotide variation (SNP) and clinical data of patients with cholangiocarcinoma were obtained from TCGA database. Patients were divided into genomic unstable (GU-like) and genomic stable (GS-like) groups according to their somatic mutations. Survival-related differential AS events were identified through integrated analysis of splicing profiling and clinical data. Kyoto Encyclopedia of Genes and Genomes enrichment analysis was used to identify AS events occurring in genes enriched in cancer pathways. Pearson correlation was applied to analyze the splicing factors regulating AS events. CIBERSORT was used identify differentially infiltrating immune cells.ResultsA prognostic signature was constructed with six AS events. Using this signature, the hazard ratio of risk score for overall survival is 2.362. For TCGA patients with cholangiocarcinoma, the area under the receiver operating characteristic curve is 0.981. CDK11A is a negative regulator of survival associated AS events. Additionally, the CD8+ T cell proportion and PD-L1 expression are upregulated in patients with cholangiocarcinoma and high splicing signatures.ConclusionWe provide a prognostic signature for cholangiocarcinoma overall survival. The CDK11A splicing factor and SLC46A1-39899-ES and IARS-86836-ES AS events may be potential targets for cholangiocarcinoma therapy. Patients with high AS risk score may be more sensitive to anti-PD-L1/PD1 immunotherapy.

Highlights

Cholangiocarcinoma describes a group of carcinomas that occur in the biliary tree
We describe a new prognostic signature model based on genomic instability derived alternative splicing (AS) events
36 patients with cholangiocarcinoma were enrolled in this study from The Cancer Genome Atlas (TCGA)

Summary

Introduction

Cholangiocarcinoma describes a group of carcinomas that occur in the biliary tree. Cholangiocarcinoma accounts for approximately 15% of all primary liver tumors and 3% of gastrointestinal cancers and the incidence of cholangiocarcinoma is increasing globally [1]. Genomic instability is a driving factor of caner [4], and is associated with poor outcome in patients with cholangiocarcinoma [5, 6]. Some microRNA (miRNA) 48 and long non-coding RNA (lncRNA) signatures associated with genomic instability have been identified. These signatures have efficiently predicted the outcome of ovarian cancer and breast carcinoma [7]. Whether alternative splicing (AS) events are associated with genomic instability remains unclear. Whether genomic instability-related alternative splicing events predicted the outcome of cholangiocarcinoma remains unclear. Genomic instability and alternative splicing (AS) events are hallmarks of carcinoma development and progression. The relationship between genomic instability, AS events, and tumor immune microenvironment remain unclear

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Results

Conclusion