Deletion and tandem duplication of exons 2-7 in the epidermal growth factor receptor gene of a human malignant glioma

The epidermal growth factor receptor (EGFR) gene is frequently amplified an d rearranged in malignant gliomas with expression of oncogenic deletion mut ants (DM). The most common mutant EGFRvIII, which contains a deletion of ex ons 2-7, is constitutively autophosphorylated and inefficiently do downregu lated. Other less common EGFR mRNA species in gliomas contain tandem duplic ation of exons, which encode the tyrosine kinase (TK) and calcium mediated receptor internalization (CAIN) domains of the molecule. We examined a pane l of human malignant gliomas and found one tumor that expressed four relate d EGFR proteins, including 125-, 140-, 170-, and 180-kDa species. This tumo r also contained four EGFR-related mRNA species, including both wild type E GFR and EGFRvIII transcripts. A third transcript contained a deletion of ex ons 2-7 and 12-13 corresponding to the 125-kDa protein. A fourth transcript contained an in-frame, tandem duplication of exons 2-7 (EGFR,TDM/2-7). The 180-kDa, tandem duplication mutant (TDM) exhibited enhanced basal phosphor ylation and impaired downregulation, In contrast to the 140-kDa EGFRvIII; h owever, phosphorylation of the 180-kDa EGFR.TDM/2-7 was strongly induced by ligand, Expression of both deletion and tandem duplication mutants in the same tumor suggests that the mechanisms responsible for DM and TDM formatio n might be closely related.