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Identification of prognostic alternative splicing signatures in uveal melanoma

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Abstract

Purpose

Alternative splicing (AS) events were reportedly associated with the development of multiple cancers. The study was designed to provide a comprehensive analysis of AS events and explore their potential prognostic value in uveal melanoma (UM).

Methods

The prognostic AS events, identified based on the data of 80 UM patients obtained from The Cancer Genome Atlas, were further screened and analyzed for construction of prognostic signatures by using LASSO regression and multivariate Cox model. Kaplan–Meier survival analysis was used to evaluate the prognostic value. The AS events-related functional pathways were explored by gene set enrichment analysis (GSEA). The difference between two subgroups in terms of treatment options was investigated. The regulatory network between prognostic AS events and splicing factors (SFs) was then constructed.

Results

A total of 1014 AS events were identified as prognostic AS events. Five prognostic AS events were involved in the construction of prognostic signatures, including AKAP2/87175/AP, RGMA/32575/ES, DNASE1L1/90581/ES, BIN1/55198/ES and ERCC2/50430/AT. UM patients were then divided into two subgroups. Prognostic AS signatures had an excellent performance in predicting the survival of UM patients, with an area under curve (AUC) of 0.962. GSEA results suggested several splicing-associated mechanisms, including cellular metabolic process and apoptosis. Low-risk subgroup could be more sensitive to drugs. A higher expression of immune checkpoint genes was observed in high-risk group than in low-risk group. SFs-AS regulatory network also revealed significant association between AS events and SFs.

Conclusions

Aberrant AS events in UM patients might serve as prognostic predictors.

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Abbreviations

AA:

Alternate acceptor

AD:

Alternate donor

AP:

Alternate promoter

AT:

Alternate terminator

AS:

Alternative splicing

AUC:

Area under curve

ES:

Exon skip

GSEA:

Gene set enrichment analysis

HR:

Hazard ration

LASSO:

The least absolute shrinkage and selection operator

ME:

Mutually exclusive exon

PSI:

Percent Spliced In

UM:

Uveal melanoma

RI:

Retained intron

RNA-seq:

RNA sequencing

ROC:

Receiver operating characteristic

SFs:

Splicing factors

TCGA:

The Cancer Genome Atlas

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Acknowledgements

The authors would like to thank the TCGA research network (http://cancergenome.nih.gov) for their efforts in making this data publicly available.

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  1. Department of Ophthalmology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Qing Yang Road 299, Wuxi, Jiangsu, 214023, China

    Xinyi Xie, Xinhua Zheng, Tianhua Xie, Jiping Cai & Yong Yao

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Correspondence to Yong Yao.

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Xie, X., Zheng, X., Xie, T. et al. Identification of prognostic alternative splicing signatures in uveal melanoma. Int Ophthalmol 41, 1347–1362 (2021). https://doi.org/10.1007/s10792-021-01699-z

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