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Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human
N Sugawa1, A J Ekstrand, C D James
1Ludwig Institute for Cancer Research, Clinical Group, Stockholm, Sweden.
Abstract:
The epidermal growth factor receptor gene has been found to be amplified and rearranged in human glioblastomas in vivo. Here we present the sequence across a splice junction of aberrant epidermal growth factor receptor transcripts derived from corresponding and uniquely rearranged genes that are coamplified and coexpressed with non-rearranged epidermal growth factor receptor genes in six primary human glioblastomas. Each of these six tumors contains aberrant transcripts derived from identical splicing of exon 1 to exon 8 as a consequence of a deletion-rearrangement of the amplified gene, the extent of which is variable among these tumors. In spite of this intertumoral variability, each intragenic rearrangement results in loss of the same 801 coding bases (exons 2-7) and creation of a new codon at the novel splice site in their corresponding transcripts. These rearrangements do not, however, affect the mRNA sequence for the signal peptide, the first five codons, or the reading frame downstream of the rearrangement.
Insights
Aberrant epidermal growth factor receptor (EGFR) gene splicing occurs in human glioblastomas. This specific exon 1 to 8 splicing results from gene rearrangements, leading to altered EGFR transcripts in tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The epidermal growth factor receptor (EGFR) gene is frequently amplified and rearranged in human glioblastomas.
- Aberrant EGFR signaling contributes to glioblastoma pathogenesis.
Purpose of the Study:
- To characterize the sequence and splicing patterns of aberrant EGFR transcripts in human glioblastomas.
- To investigate the relationship between gene rearrangement and transcript formation in glioblastoma.
Main Methods:
- Sequence analysis of aberrant EGFR transcripts from six primary human glioblastomas.
- Identification of splice junctions in rearranged EGFR genes.
Main Results:
- Identical splicing of exon 1 to exon 8 was observed in aberrant EGFR transcripts across all six tumors.
- Gene rearrangements involved deletions and resulted in the loss of coding bases (exons 2-7).
- A novel splice site was created, altering the transcript sequence without affecting the signal peptide or downstream reading frame.
Conclusions:
- Specific EGFR gene rearrangements lead to consistent aberrant transcript formation in glioblastomas.
- These findings elucidate a mechanism of EGFR dysregulation in glioblastoma development.