Alternative Splicing Events and Splicing Factors Are Prognostic in Adrenocortical Carcinoma.

Jian Lv,Zhihua Wang,Lili Li,Yuan He

doi:10.3389/fgene.2020.00918

Jian Lv, Zhihua Wang + Show 2 more

Open Access

https://doi.org/10.3389/fgene.2020.00918

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Abstract

Alternative splicing is involved in the pathogenesis of human diseases, including cancer. Here, we investigated the potential application of alternative splicing events (ASEs) and splicing factors (SFs) in the prognosis of adrenocortical carcinoma (ACC). Transcriptome data from 79 ACC cases were downloaded from The Cancer Genome Atlas database, and percent spliced-in values of seven splicing types were downloaded from The Cancer Genome Atlas SpliceSeq database. By the univariate Cox regression analysis, 1,839 survival-related ASEs were identified. Prognostic indices based on seven types of survival-related ASEs were calculated by multivariate Cox regression analysis. Survival curves and receiver operating characteristic curves were used to assess the diagnostic value of the prognostic model. Independent prognosis analysis identified several ASEs (e.g., THNSL2| 54469| ME) that could be used as biomarkers to predict the prognosis of patients with ACC accurately. By analyzing the co-expression correlation between SFs and ASEs, 188 highly correlated interactions were established. From the protein interaction network, we finally screened six hub SFs, including YBX1, SART1, PRCC, SNRPG, SNRPE, and SF3B4, whose expression levels were significantly related to the overall survival and prognosis of ACC. Our findings provide a reliable model for predicting the prognosis of ACC patients based on aberrant alternative splicing patterns.

Highlights

Alternative splicing of pre-messenger RNA produces transcript isoforms for 95% of human genes, increases protein diversity, and provides functional diversity at various regulation level (Pan et al, 2008)
Transcriptome data from the The Cancer Genome Atlas (TCGA) database provide identity information for up to 56,754 transcripts, which represents a key resource for exploring alternative splicing events (ASEs) in tumors concurrently deposited in the database
Individual ASE is assigned a unique annotation in the TCGA SpliceSeq database; for instance, in the term CIRBP| 46443| exon skip (ES), CIRBP is the official gene symbol, 46443 is the unique ID number of a specific ASE, and ES represents the type of the alternative splicing pattern

Summary

Introduction

Alternative splicing of pre-messenger RNA (mRNA) produces transcript isoforms for 95% of human genes, increases protein diversity, and provides functional diversity at various regulation level (Pan et al, 2008). Aberrant alternative splicing events (ASEs) have been frequently observed in cancers and is recognized as an important signature for tumorigenesis and related pathologies, such as initiation and development of cancer (Oltean and Bates, 2014; Chen and Weiss, 2015; Lee and Abdel-Wahab, 2016), ASEs and SFs in ACC cancer metabolism (Kozlovski et al, 2017), cancer immunotherapy (Frankiw et al, 2019), cancer drug resistance (Siegfried and Karni, 2018), and so on. Recent studies highlighted that specific molecular signatures could predict the survival and prognosis of ACC patients, which came from genomic approaches, including transcriptome, exome or whole-genome sequencing, chromosome alterations, methylome, and miRnome (Barreau et al, 2013; Patel et al, 2013; Assie et al, 2014; Szabo et al, 2014; Jouinot and Bertherat, 2018).

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