Structure of the Epidermal Growth Factor Receptor Gene and Intron Recombination in Human Gliomas

Michael   J.   Ciesielski; Robert   A.   Fenstermaker

Abstract

The epidermal growth factor receptor (EGFR) is a membrane-anchored, 170 kDa, protein tyrosine kinase that has been implicated in tumorigenesis. Recent sequence data from the publicly funded Human Genome Project has led to a revision in the structure of the EGFR gene, as well as an improved understanding of its mutations in tumor cells. The exons and introns of the EGFR gene are contained within 168 kilobases of DNA, including a completely sequenced 123-kilobase first intron. The EGFR gene is frequently amplified and rearranged in malignant gliomas with expression of oncogenic deletion (DM) and tandem duplication (TDM) mutants. The most common mutant is EGFRvIII, which arises from recombination between introns 1 and 7 with deletion of intervening sequences. Some human gliomas express 185 kDa and 190 kDa EGFR tandem duplication mutants with constitutive functional activity. These tumors contain EGFR genes with an in-frame tandem duplication of exons 18 through 25 or exons 18 through 26 respectively. Th e TDM also arise from recombination between flanking introns 17 and either 25 or 26. DM and TDM have been found in the same tumors, suggesting that the mechanisms responsible for both types of mutants may be closely related. Each of the introns involved in tumor-specific recombination contain sequences with homology to the recombination signal sequence (RSS) heptamers present in the V(D)J region of the immunoglobulin and T lymphocyte antigen receptor genes. These observations suggest a possible mechanism for oncogenic EGFR gene recombination in malignant gliomas.