Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails.

Abstract

This study describes genomic rearrangements near the 3' end of the epidermal growth factor receptor (EGFR) gene in eight glioblastomas displaying coamplification and expression of both normal and rearranged EGFR. In four of these cases, it was possible by PCR to amplify tumor EGFR cDNA, which allowed sequence determination of the 3' transcript alterations associated with the rearrangements. Such analysis revealed that the four cases have in common a deletion of 255 bases that encode a portion of the receptor's cytoplasmic domain. The remaining four cases revealed genomic rearrangements in the same region of the gene as those described above and revealed aberrant EGFR transcripts lacking the same 255 bases determined to be missing in the sequenced EGFR cDNAs as well as large regions of contiguous downstream sequences. Therefore, all of the eight cases described here express transcripts that do not encode large C-terminal, intracellular portions of the receptor. In three of the eight cases, the EGFR transcripts displaying a 3' alteration also displayed a 5' inframe deletion of sequences encoding a portion of the extracellular domain, and for one of the corresponding patients it was possible to determine that the two transcript alterations were acquired as separate events. We have now detected the 5' and/or 3' alterations in 21 of 32 cases of glioblastoma with EGFR amplification; no genetic alterations have been detected in glioblastomas without EGFR amplification. In combination with previously published reports, these data suggest the in vivo evolution of EGFR toward an increasingly oncogenic potential through gene amplification with subsequent and successive gene alterations.

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

“…Intriguingly, unlike wild‐type EGFR, our data clearly demonstrate that tyrosine phosphorylation‐impaired CYF10 EGFR mutants are still able to transform NIH‐3T3 and Ba/F3 cells, suggesting that constitutive phosphorylation on mutant EGFR may be dispensable for their transforming potential. These paradoxical results are consistent with our reports that a subset of mutant EGFR is capable of cellular transformation irrespective of asymmetric dimerization16 and that various C‐terminal intragenic deletion mutants identified in glioblastomas and lung adenocarcinoma are oncogenic 29, 30. Furthermore, an Ex19Del mutant was shown to retain its oncogenic activity in the absence of the C‐terminal domain or autophosphorylation,23, 24 putatively through heterodimerization of phosphorylated ErbB3 with C‐terminal domain deleted Ex19Del.…”

Trans receptor inhibition of human glioblastoma cells by erbB family ectodomains

“…Amplification and͞or alteration of the epidermal growth factor receptor (EGFr) gene is frequently observed in glial tumor progression (1,2), particularly in glioblastoma, the most malignant glial tumor (3)(4)(5)(6)(7)(8). A significant proportion of these tumors show EGFr amplification with or without gene alteration (2)(3)(4), and this has been correlated with a shorter interval to disease recurrence and poorer survival (8).…”

“…A significant proportion of these tumors show EGFr amplification with or without gene alteration (2)(3)(4), and this has been correlated with a shorter interval to disease recurrence and poorer survival (8).…”

EGFR mutations predict a favorable outcome for malignant pleural effusion of lung adenocarcinoma with Tarceva therapy

“…For example, geographic (ethnic) differences in detection of the EGFR mutation may result in variability. The results of previous studies (30,34,42,(61)(62)(63)(64)(65)(66) showed that there were significant differences in the sites and main types of EGFR mutations in different races and regions. Most of the specimens in this study came from Shandong, China.…”