Characterization of progression-related alternative splicing events in testicular germ cell tumors

• Published in: Asian journal of andrology Vol. 23; no. 3; pp. 259 - 265
• Main Authors: Zhang, Chuan-Jie, Li, Zong-Tai, Shen, Kan-Jie, Chen, Lu, Xu, Dan-Feng, Gao, Yi
• Format: Journal Article
• Language: English
• Published: China Wolters Kluwer India Pvt. Ltd 01.05.2021; Medknow Publications & Media Pvt. Ltd; Wolters Kluwer - Medknow; Wolters Kluwer Medknow Publications
• Subjects: alternative splicing events; network; progression-free survival-related model; testicular germ cell tumor; Original; Tumors; progression-free survival-related model; testicular germ cell tumor; alternative splicing events; network
• ISSN: 1008-682X; 1745-7262
• DOI: 10.4103/aja.aja_30_20

Accumulating evidence supports the significance of aberrant alternative splicing (AS) events in cancer; however, genome-wide profiling of progression-free survival (PFS)-related AS events in testicular germ cell tumors (TGCT) has not been reported. Here, we analyzed high-throughput RNA-sequencing data and percent-spliced-in values for 150 patients with TGCT. Using univariate and multivariate Cox regression analysis and a least absolute shrinkage and selection operator method, we identified the top 15 AS events most closely associated with disease progression. A risk-associated AS score (ASS) for the 15 AS events was calculated for each patient. ASS, pathological stage, and T stage were significantly associated with disease progression by univariate analysis, but only ASS and pathological stage remained significant by multivariate analysis. The ability of these variables to predict 5-year progression was assessed using receiver operating characteristic curve analysis. ASS had stronger predictive value than a combination of age, pathological stage, and T stage (area under the curve = 0.899 and 0.715, respectively). Furthermore, Kaplan-Meier analysis of patients with low and high ASS demonstrated that high ASS was associated with significantly worse PFS than low ASS (P = 1.46 × 10−7). We also analyzed the biological functions of the PFS-related AS-related genes and found enrichment in pathways associated with DNA repair and modification. Finally, we identified a regulatory network of splicing factors with expression levels that correlated significantly with AS events in TGCT. Collectively, this study identifies a novel method for risk stratification of patients and provides insight into the molecular events underlying TGCT.