A widespread length-dependent splicing dysregulation in cancer

Author:

Zhang Sirui1ORCID,Mao Miaowei1ORCID,Lv Yuesheng2,Yang Yingqun13,He Weijing45ORCID,Song Yongmei6ORCID,Wang Yongbo7ORCID,Yang Yun1,Al Abo Muthana8,Freedman Jennifer A.89ORCID,Patierno Steven R.89ORCID,Wang Yang2ORCID,Wang Zefeng1ORCID

Affiliation:

1. CAS Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

2. Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.

3. Shanghai Tech University, Shanghai 200031, China.

4. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

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

7. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

8. Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA.

9. Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

Dysregulation of alternative splicing is a key molecular hallmark of cancer. However, the common features and underlying mechanisms remain unclear. Here, we report an intriguing length-dependent splicing regulation in cancers. By systematically analyzing the transcriptome of thousands of cancer patients, we found that short exons are more likely to be mis-spliced and preferentially excluded in cancers. Compared to other exons, cancer-associated short exons (CASEs) are more conserved and likely to encode in-frame low-complexity peptides, with functional enrichment in GTPase regulators and cell adhesion. We developed a CASE-based panel as reliable cancer stratification markers and strong predictors for survival, which is clinically useful because the detection of short exon splicing is practical. Mechanistically, mis-splicing of CASEs is regulated by elevated transcription and alteration of certain RNA binding proteins in cancers. Our findings uncover a common feature of cancer-specific splicing dysregulation with important clinical implications in cancer diagnosis and therapies.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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