The prognostic significance of global aberrant alternative splicing in patients with myelodysplastic syndrome

Yi-Tsung Yang,Cheng-Hong Tsai,Hwei-Fang Tien,Hsin-An Hou,Yu-Chiao Chiu,Chein-Jun Kao,Mei-Hsuan Tseng,Wen-Chien Chou,Chien-Chin Lin

doi:10.1038/s41408-018-0115-2

Yi-Tsung Yang, Cheng-Hong Tsai + Show 7 more

Open Access

https://doi.org/10.1038/s41408-018-0115-2

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Abstract

Aberrant alternative splicing (AS) is a hallmark of cancer development. However, there are limited data regarding its clinical implications in myelodysplastic syndrome (MDS). In this study, we performed an in-depth analysis of global AS in 176 primary MDS patients with 20 normal marrow transplant donors as reference. We found that 26.9% of the expressed genes genome-wide were aberrantly spliced in MDS patients compared with normal donors. These aberrant AS genes were related to pathways involved in cell proliferation, cell adhesion and protein degradation. A higher degree of global aberrant AS was associated with male gender and U2AF1 mutation, and predicted shorter overall survival and time to leukemic change. Moreover, it was an independent unfavorable prognostic factor irrespective of age, revised international prognostic scoring system (IPSS-R) risk, and mutations in SRSF2, ZRSR2, ASXL1, TP53, and EZH2. With LASSO-Cox regression method, we constructed a simple prognosis prediction model composed of 13 aberrant AS genes, and demonstrated that it could well stratify MDS patients into distinct risk groups. To our knowledge, this is the first report demonstrating significant prognostic impacts of aberrant splicing on MDS patients. Further prospective studies in larger cohorts are needed to confirm our observations.

Highlights

Alternative splicing (AS) is a physiological phenomenon to ensure higher protein diversity for better environmental fit
Study design and patient cohort From November 1991 to December 2010, a total of 176 primary myelodysplastic syndrome (MDS) patients who were diagnosed at the National Taiwan University Hospital (NTUH) and had available samples and complete clinical and gene mutation data were enrolled in this study
In order to clarify the pathological effects of aberrant splicing in the absence of mutations in either spliceosome complex or epigenetic modifiers, which were common in MDS patients[22], we focused on subgroups of MDS patients without detectable mutations in genes related to spliceosome or epigenetic modifications and found that a higher global aberrant AS score could predict shorter overall survival (OS) in these patients (Fig. 3c)

Summary

Introduction

Alternative splicing (AS) is a physiological phenomenon to ensure higher protein diversity for better environmental fit. Splicing is a complex and tightly regulated process. Perturbation of this process by spliceosome gene mutations, epigenetic modifications, or other causes would lead to aberrant AS, resulting in deregulation of many cellular processes, such as cell proliferation, adhesion, differentiation, motility, invasion, and death[2,3]. The genes with aberrant AS encode several oncoproteins, tumor suppressor proteins, ribonucleoproteins, and proteins involved in apoptosis, cell proliferation, and spliceosome assembly[5,6]. These findings provide a link between aberrant AS and AML pathogenesis

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