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The landscape and biological relevance of aberrant alternative splicing events in esophageal squamous cell carcinoma

Oncogene volume 40, pages 4184–4197 (2021)Cite this article

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Abstract

Aberrant alternative splicing events (AASEs) are key biological processes for tumorigenesis and the rationale for designing splice-switching oligonucleotides (SSOs). However, the landscape of AASEs in esophageal squamous cell carcinoma (ESCC) remains unclear, which undermines the development of SSOs for ESCC. Here, we profiled AASEs based on 125 pairs of RNA-seq libraries. We identified 14,710 AASEs in ESCC, most of which (92.67%) affected coding genes. The first exon of transcripts was frequently changed in ESCC. We constructed a regulatory network where 74 RNA-binding proteins regulated 2142 AASEs. This network was enriched in apoptotic pathways and various adhesion/junction-related processes. Somatic mutations in ESCC regulating ASEs were mainly through trans-regulatory mode and were enriched in intron regions. Isoform switches of apoptotic genes and binding genes both tended to induce “noncoding transcripts” and “domain loss,” disrupting the apoptotic and Hippo signaling pathways. All ESCC samples were grouped into three clusters with different AASEs patterns and the second cluster was identified as “cold tumor,” with a low abundance of immune cells, activated immune pathways, and immunomodulators. Our work comprehensively profiled the landscape of AASEs in ESCC, revealed novel AASEs related to tumorigenesis and immune microenvironment, and suggested promising directions for designing SSOs for ESCC.

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Fig. 1: Overview of aberrant alternative splicing events (AASEs) and related genes in ESCC.
Fig. 2: Regulation of AASEs by RNA-binding proteins (RBPs).
Fig. 3: Regulation of ASEs by somatic mutations.
Fig. 4: Details of apoptotic genes associated with AASEs.
Fig. 5: Details of binding genes associated with AASEs.
Fig. 6: Alternative splicing is related to the tumor immune microenvironment.

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Data availability

Genomic and transcriptomic data are available under accession no. PRJCA002085 in the Genome Sequence Archive of Beijing Institute of Genomics, Chinese Academy of Sciences.

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Acknowledgements

This research was supported by the Research Fund of Key Laboratory of Xinjiang oncology (Grant no. 2017D04006). Funders only provided funding and had no role in the study design, data collection, data analysis, interpretation, and writing of the report. The authors thank Dr Wen Zhang (Department of Immunology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China) for providing technical assistance.

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Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Quanyou Wu & Kaitai Zhang

  2. Key Laboratory of Oncology of Xinjiang Uyghur Autonomous Region, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China

    Yuan Zhang, Wei Sun, Ruozheng Wang & Meng Liu

  3. Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China

    Haiyin An

  4. Key Laboratory of Cancer Immunotherapy and Radiotherapy, Chinese Academy of Medical Sciences, Urumqi, 830011, Xinjiang, China

    Ruozheng Wang & Meng Liu

  5. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China

    Ruozheng Wang & Meng Liu

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  1. Quanyou Wu
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Wu, Q., Zhang, Y., An, H. et al. The landscape and biological relevance of aberrant alternative splicing events in esophageal squamous cell carcinoma. Oncogene 40, 4184–4197 (2021). https://doi.org/10.1038/s41388-021-01849-8

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