Genetic-informed alternative RNA splicing serves an essential role in carcinogenesis and prognosis of non-small-cell lung cancer

Hanyi Zhou; Ming Wu; Kui Wu; Qilong Tan; Xiaohang Xu; Mengying Wang; Liyang Sun; Yuanxing Tu; Weifang Zheng; Yun Zhu; Huakang Tu; Dan Zhou; Xifeng Wu

doi:10.59717/j.xinn-med.2025.100111

The Innovation Medicine > 2025 Vol. 3 > No. 1 > 100111

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Genetic-informed alternative RNA splicing serves an essential role in carcinogenesis and prognosis of non-small-cell lung cancer

1.
Center of Clinical Big Data and Analytics of the Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
2.
Zhejiang Key Laboratory of Intelligent Preventive Medicine, Hangzhou 310058, China
3.
Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
4.
HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou 310018, China
5.
Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
6.
The Second Affiliated Hospital of Zhejiang University School of Medicine, Lanxi Branch (Lanxi People’s Hospital), Lanxi 321100, China
7.
Lanxi Hospital of Traditional Chinese Medicine, Lanxi 321102, China
8.
National Institute for Data Science in Health and Medicine, Zhejiang University, Hangzhou 310058, China

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Corresponding authors: xifengw@zju.edu.cn (X.W.); danzhou@zju.edu.cn (D.Z.)
Received Date: September 20, 2024

Accepted Date: January 07, 2025

Published Online: January 16, 2025

The Innovation Medicine 3(1), https://doi.org/10.59717/j.xinn-med.2025.100111 | Cite this article

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GRAPHICAL ABSTRACT

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. Lung cancer is the most commonly diagnosed malignancy both in China and globally.
  
  RNA splicing plays a substantial role in influencing cancer heritability.
  
  Genetic-based splicing dysregulation significantly contributes to the carcinogenesis and prognosis of lung cancer.

ABSTRACT

ABSTRACT

Dysregulated RNA splicing is a post-transcriptional molecular feature that significantly influences tumor progression and prognosis. However, the role of alternative splicing in the development of non-small cell lung cancer (NSCLC) within the Chinese population remains poorly understood. In this study, we investigated the genetic regulation of splicing in 245 tumor and 297 normal lung tissue samples from Chinese NSCLC patients. By integrating splicing data with a meta-analyzed genome-wide association study (GWAS) for NSCLC in East Asians (7,035 cases and 185,413 controls), we identified 14 novel NSCLC-associated splicing events (FDR < 0.05) through a splicing transcriptome-wide association study (spTWAS). Additionally, we validated the involvement of the splicing gene FARP1 and the EIF3 family, both of which have been associated with NSCLC risk. By combining the results of differential splicing analysis and spTWAS, followed by colocalization analysis and putative splicing factor predictions, we highlighted the critical roles of splicing events in TP63 (1st exon skipping) and TPM1 (6th exons mutually exclusive) in NSCLC, bridging the missing biology between SNP-NSCLC association. Furthermore, we underscored several splicing events in genes including ILK, which were also associated with NSCLC prognosis. In conclusion, this study elucidated the genetic architecture of splicing in lung tissues and revealed the significant contribution of splicing dysregulation to the carcinogenesis and prognosis of NSCLC.

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Zhou H., Wu M., Wu K., et al. (2025). Genetic-informed alternative RNA splicing serves an essential role in carcinogenesis and prognosis of non-small-cell lung cancer. The Innovation Medicine 3:100111. https://doi.org/10.59717/j.xinn-med.2025.100111

Zhou H., Wu M., Wu K., et al. (2025). Genetic-informed alternative RNA splicing serves an essential role in carcinogenesis and prognosis of non-small-cell lung cancer. The Innovation Medicine 3:100111. https://doi.org/10.59717/j.xinn-med.2025.100111

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Genetic-informed alternative RNA splicing serves an essential role in carcinogenesis and prognosis of non-small-cell lung cancer

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