Identical splicing ofaberrant epidermal growth factor receptor transcripts fromamplified rearranged genesin

Theepidermal growth factor receptor gene hasbeenfoundtobeamplified andrearranged inhuman glioblastomas invivo. Herewepresent thesequence across a splice junction ofaberrant epidermal growth factor receptor transcripts derived fromcorresponding anduniquely rear- ranged genes that arecoamplified andcoexpressed withnon- rearranged epidermal growth factor receptor genes insix primary humanglioblastomas. Eachofthese sixtumors con- tains aberrant transcripts derived fromidentical splicing of exon1toexon8asaconsequence ofadeletion-rearrangement oftheamplified gene, theextent ofwhich isvariable among these tumors. Inspite ofthis intertumoral variability, each intragenic rearrangement results inloss ofthesame801coding bases (exons 2-7) andcreation ofanewcodon atthenovel splice site intheir corresponding transcripts. These rearrangements donot,however, affect themRNA sequence forthesignal peptide, thefirst five codons, orthereading frame downstream oftherearrangement. Thenormal epidermal growth factor receptor (EGFR)gene product isa170-kDa transmembrane glycoprotein found on manynormal andmalignant cells (1-7). Theextracellular binding ofoneofits twoknownendogenous ligands, epider- malgrowth factor andtransforming growth factor a,results inconformational changes oftheextracellular domain (8), the activation ofthereceptor's intracellular tyrosine kinase ac- tivity (9,10), andthestimulation ofDNA synthesis. A constitutively activated andcell-transformin g