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Global profiling of alternative splicing in non-small cell lung cancer reveals novel histological and population differences

Oncogene volume 44, pages 958–967 (2025)Cite this article

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Abstract

Lung cancer is one of the most frequently diagnosed cancers in the US. African-American (AA) men are more likely to develop lung cancer with higher incidence and mortality rates than European-American (EA) men. Herein, we report high-confidence alternative splicing (AS) events from high-throughput, high-depth total RNA sequencing of lung tumors and non-tumor adjacent tissues (NATs) in two independent cohorts of patients with adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). We identified novel AS biomarkers with notable differential percent spliced in (PSI) values between lung tumors and NATs enriched in the AA and EA populations, which were associated with oncogenic signaling pathways. We also uncovered tumor subtype- and population-specific AS events associated with cell surface proteins and cancer driver genes. We highlighted significant AS events in SYNE2 specific to LUAD in both populations, as well as those in CD44 from EAs and TMBIM6 from AAs specific to LUAD. Here, we also present the validation of cancer signatures based on direct high-throughput reverse transcription-PCR. Our large survey of lung tumors presents a rich data resource that may help to understand molecular subtypes of lung tumor between AAs and EAs and reveal new therapeutic vulnerabilities that potentially advance health equity.

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Fig. 1: Profiling of AS events in lung cancer.
Fig. 2: Population differences in alternatively spliced events in LUAD.
Fig. 3: Population differences in alternatively spliced events in LUSC.
Fig. 4: Alternative spliced isoforms detected in cancer driver genes in tumor histologies and populations.
Fig. 5: Alternative spliced isoforms detected in surface proteins in histologies.
Fig. 6: Alternative spliced isoforms detected in surface proteins in populations.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information files and from the corresponding authors on request.

Code availability

All scripts for analysis and figure production were built in-house and provided on GitHub (https://github.com/iamsamanzeeshan/LungSplicingAAvsEA).

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Funding

This work was supported by a grant from the National Cancer Institute (R01 CA239093) to SRP, HK, BMR, and the Rutgers Cancer Institute of New Jersey Cancer Health Equity Pilot Award to SRP and HK, and Biomedical Informatics Shared Resource at the Rutgers Cancer Institute (P30CA072720-5917).

Author information

Author notes

  1. Saman Zeeshan

    Present address: Department of Biomedical and Health Informatics, School of Medicine, University of Missouri, Kansas City, USA

  2. Sharon R. Pine

    Present address: Department of Medicine, University of Colorado School of Medicine, University of Colorado Cancer Center, Aurora, USA

Authors and Affiliations

  1. Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, USA

    Saman Zeeshan, Hossein Khiabanian & Sharon R. Pine

  2. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, USA

    Bhavik Dalal, Rony F. Arauz, Adriana Zingone, Curtis C. Harris & Bríd M. Ryan

  3. Department of Pathology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, USA

    Hossein Khiabanian

  4. Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, USA

    Sharon R. Pine

  5. Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, USA

    Sharon R. Pine

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Contributions

BMR conceived and supervised the project, wrote, and revised the manuscript, and acquired funding for this study. SZ designed the study and performed bioinformatic analyzes, including data analysis, writing, and revising the manuscript, and preparing figures. SRP conceived and supervised the project, revised, and edited the manuscript, and acquired funding for this study. HK supervised the project, revised, and edited the manuscript, and acquired the funding for this study. CCH supervised and BD performed the validation experiments. RFA and AZ designed experiments and provided technical and sequencing assistance.

Corresponding authors

Correspondence to Sharon R. Pine or Bríd M. Ryan.

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Ethics approval and consent to participate

The NCI-MD data that supported the findings of this study were derived from patients enrolled in the NCI-MD case-control study [11]. This study was conducted in accordance with the principles of the Declaration of Helsinki. Institutional review board approval was granted by the National Cancer Institute, Bethesda, Maryland, and the participating hospitals. This study was registered at clinicaltrials.gov [https://clinicaltrials.gov/ct2/show/NCT00339859]. Informed consent was obtained from all participants.

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Zeeshan, S., Dalal, B., Arauz, R.F. et al. Global profiling of alternative splicing in non-small cell lung cancer reveals novel histological and population differences. Oncogene 44, 958–967 (2025). https://doi.org/10.1038/s41388-024-03267-y

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