Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma
Open accessAbstract
We recently reported a significant relationship between tumor cell expression of the ERBB4 receptor, the most recently described member of the epidermal growth factor receptor family, and aggressive tumor phenotype in childhood medulloblastoma. Two alternative juxtamembrane (JM) isoforms of the ERBB4 receptor have been described. Termed JMa and JMb, these variants possess different receptor processing and ligand-binding characteristics. In the current study, we employed an RT-PCR and sequencing strategy to determine the pattern of ERBB4 JM isoform expression in a large (n = 78) series of pediatric medulloblastomas. JMa and JMb transcript expression was detected in 53% and 28% of tumor samples, respectively. In addition, two novel ERBB4 JM isoforms, which we have termed JMc and JMd, were isolated from 10% and 36% of tumors, respectively. Sequence analysis revealed the JMc transcript to contain a deletion of the entire JM region. In contrast, JMd includes an extended coding region, retaining both the JMa and JMb sequences. Neither of these novel isoforms was detected in normal human adult cerebellum, but expression of JMd was observed in developing fetal cerebellum, suggesting that this later isoform may represent an ERBB4 transcript restricted to primitive neuroectoderm-derived tissue. To confirm that the four ERBB4 JM isoforms arise by alternative RNA splicing, we sequenced the intron-exon junctions of the human ERBB4 gene within the JM region. This demonstrated the four ERBB4 JM variants to be encoded by two short exons containing the JMb and JMa sequences positioned in the order 5' to 3' and separated by a 121 bp intron.
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Mutations in ERBB4 were identified in cancer, particularly melanoma, lung adenocarcinoma, and medulloblastoma.
“Similarly, mutations in ERBB4 were identified in cancer, particularly melanoma (Prickett et al., 2009), lung adenocarcinoma (Ding et al., 2008), and medulloblastoma (Gilbertson et al., 2001).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Gilbertson et al., 2001
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- Authors
- Gilbertson, R., Hernan, R., Pietsch, T., Pinto, L., Scotting, P., Allibone, R., Ellison, D., Perry, R., Pearson, A., & Lunec, J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Bonn (DE)
- Newcastle University (GB)
- University of Nottingham (GB)
- Southampton General Hospital (GB)
- Newcastle upon Tyne Hospital (GB)
- Royal Victoria Infirmary (GB)
- Corresponding author
- Gilbertson, Richard
- Venue
- Genes Chromosomes and Cancer
- Publisher
- Wiley
- Published
- 2001-05-30
- Volume
- 31
- Issue
- 3
- Pages
- 288-294
- ISSN
- 1045-2257 (ISSN-L)
- 1098-2264
- OpenAlex
- W2139574983
- Cited by
- 60
- References
- 14
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 4 · 2016: 2 · 2015: 4 · 2014: 3 · 2013: 2
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Genes Chromosomes and Cancer (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Keywords
- ErbB4, alternative splicing, novel isoforms, epidermal growth factor receptor family, tumor aggressiveness, fetal cerebellum, exon-intron junctions
- MeSH terms
- Amino Acid Sequence, Base Sequence, Child, Child, Preschool, Female, Humans, Male, Medulloblastoma, Molecular Sequence Data, Neoplasm Proteins, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Alternative Splicing, Protein Isoforms, ErbB Receptors, Receptor, ErbB-4
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