EGFR Intron Recombination in Human Gliomas: Inappropriate Diversion of V(D)J Recombination?
The epidermal growth factor receptor (EGFR) is a membrane-bound, 170 kDa, protein tyrosine kinase that plays an important role in tumorigenesis. The EGFR gene, which is composed of over 168 kb of sequence, including a 123-kb first intron, is frequently amplified and rearranged in malignant gliomas leading to the expression of oncogenic deletion (DM) and tandem duplication (TDM) mutants. The most common DM in gliomas is EGFRvIII, which arises from recombination between introns 1 and 7 with deletion of exons 2 through 7 and intervening introns. In addition, some human gliomas express 180- to 190-kDa TDM, which are constitutively active and highly oncogenic. Both DM and TDM arise by recombination of introns that contain sequences with homology to the recombination signal sequence (RSS) heptamers and nonamers present in the V(D)J region of the immunoglobin and T lymphocyte antigen receptor genes. V(D)J RSS have also been identified in certain proto-oncogenes like bcl-2 that are involved in translocations associated with the development of human lymphomas and in other genes such as hypoxanthine-guainine phosphoribosyl transferase (HPRT) in which deletion mutations and intron rearrangements are a common phenomenon. Together with the expression of recombination associated gene (RAG) and nonhomologous end-joining (NHEJ) proteins in gliomas, these observation suggest that aberrant activity of the V(D)J recombinase may be involved in the activation of proto-oncogenes in both liquid and solid tumors.
Fenstermaker
Robert A
RA
Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Ciesielski
Michael J
MJ