Identification of survival-associated alternative splicing events and signatures in adrenocortical carcinoma based on TCGA SpliceSeq data.

Ning Xu,Yong Wei,Yu-Peng Wu,Ye-Hui Chen,Zhi-Bin Ke,Shao-Hao Chen,Xiao-Dan Lin,Qing-Shui Zheng,Fei Lin

doi:10.18632/aging.102924

Abstract

Objective: To explore the correlations among alternative splicing (AS), splicing factors (SF) and survival outcome in adrenocortical carcinoma (ACC) patients.Results: A total of 92 ACC patients were included. Univariate analysis identified 3919 AS events significantly associated with overall survival. Lasso method followed by multivariate analysis revealed that the prognostic capacity of these survival-related AS events is satisfactory. Interestingly, we found that the area under the curve (AUC) of AA, AD, AP and RI were more than 0.9, indicating that these four types of AS were of great significance. Independent prognostic analysis showed that only the risk score was the independent risk factor of ACC survival. Finally, we constructed an interesting interaction network between AS and SF.Conclusions: This is the first and most comprehensive study to explore the aberrant AS variants in ACC, which might provide novel insights into molecular mechanism of ACC.Methods: The transcriptome data, clinical information and Percent Spliced In (PSI) values of the ACC were obtained from TCGA database and TCGA SpliceSeq data portal. Lasso method and uni/multivariate Cox regression analysis were used to identify survival-related AS events and develop multi-AS-based signatures. The relationship between AS events and SFs was also investigated.

Highlights

As a rare but greatly aggressive malignancy, the prognosis of adrenocortical carcinoma (ACC) is rather poor [1, 2]
A total of 92 ACC patients from the Cancer Genome Atlas (TCGA) database were included in the present study
The alternative splicing (AS) events were comprehensively analyzed. Intersections among these seven types of AS events and quantitative analysis of these interactive sets were presented by the UpSet plot (Figure 1A). These data suggested that a single gene could possess several types of mRNA splicing events and exon skip (ES) was the predominant type in ACC cohort whereas mutually exclusive exons (ME) was rare

Summary

Introduction

As a rare but greatly aggressive malignancy, the prognosis of adrenocortical carcinoma (ACC) is rather poor [1, 2]. There have been numerous studies exploring ACC, the specific molecular mechanism has not been fully elucidated. As the most important post-transcriptional regulatory process, alternative splicing (AS) modifies more than 90% of human genes [5, 6], contributing greatly to protein diversity and complexity [7]. Numerous physiological and pathological behaviors in the human body are related to AS, including angiogenesis, proliferation, hypoxia, etc [5, 8, 9]. It was reported that survival predictors of gene expression were consistently inferior to AS-based survival predictors [10]. Little work has been devoted to investigate the role of AS in ACC

Methods

Results

Conclusion