An ErbB2 splice variant lacking exon 16 drives lung carcinoma
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Updated: Dec 13, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Harvey W Smith1, Lei Yang2,3, Chen Ling2
1Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; william.muller@mcgill.ca harvey.smith2@mcgill.ca.
Abstract:
Lung cancer causes more deaths annually than any other malignancy. A subset of non-small cell lung cancer (NSCLC) is driven by amplification and overexpression or activating mutation of the receptor tyrosine kinase (RTK) ERBB2 In some contexts, notably breast cancer, alternative splicing of ERBB2 causes skipping of exon 16, leading to the expression of an oncogenic ERBB2 isoform (ERBB2ΔEx16) that forms constitutively active homodimers. However, the broader implications of ERBB2 alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevated ERBB2ΔEx16 expression in a subset of NSCLC cases, as well as splicing site mutations facilitating exon 16 skipping and deletions of exon 16 in a subset of these lung tumors and in a number of other carcinomas. Supporting the potential of ERBB2ΔEx16 as a lung cancer driver, its expression transformed immortalized lung epithelial cells while a transgenic model featuring inducible ERBB2ΔEx16 specifically in the lung epithelium rapidly developed lung adenocarcinomas following transgene induction. Collectively, these observations indicate that ERBB2ΔEx16 is a lung cancer oncogene with potential clinical importance for a proportion of patients.
Insights
A novel lung cancer oncogene, ERBB2ΔEx16, has been identified. This ERBB2 variant drives tumor formation and may be clinically important for some non-small cell lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Lung cancer is the leading cause of cancer mortality.
- Non-small cell lung cancer (NSCLC) can be driven by receptor tyrosine kinase (RTK) ERBB2 alterations.
- ERBB2 alternative splicing, including exon 16 skipping, is known in breast cancer but its role in other cancers is unexplored.
Purpose of the Study:
- To investigate the role of ERBB2 alternative splicing in human cancers, particularly NSCLC.
- To identify and characterize the oncogenic ERBB2ΔEx16 isoform in lung cancer.
Main Methods:
- Genomic and transcriptomic analysis of NSCLC patient samples.
- Functional studies using immortalized lung epithelial cells.
- Development and analysis of a transgenic mouse model with inducible ERBB2ΔEx16 expression in lung epithelium.
Main Results:
- Elevated ERBB2ΔEx16 expression was found in a subset of NSCLC cases.
- Splicing site mutations and exon 16 deletions were identified in lung tumors and other carcinomas.
- ERBB2ΔEx16 expression transformed lung epithelial cells in vitro.
- Transgenic mice rapidly developed lung adenocarcinomas upon ERBB2ΔEx16 induction.
Conclusions:
- ERBB2ΔEx16 acts as a lung cancer oncogene.
- This ERBB2 isoform has potential clinical significance for a subset of NSCLC patients.
- Further research into ERBB2ΔEx16 as a therapeutic target is warranted.
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