Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Apr 1;89(7):2965–2969. doi: 10.1073/pnas.89.7.2965

Structural alterations of the epidermal growth factor receptor gene in human gliomas.

A J Wong 1, J M Ruppert 1, S H Bigner 1, C H Grzeschik 1, P A Humphrey 1, D S Bigner 1, B Vogelstein 1
PMCID: PMC48784  PMID: 1557402

Abstract

The epidermal growth factor receptor (EGFR) gene is amplified in 40% of malignant gliomas, and the amplified genes are frequently rearranged. We have characterized the genetic alterations associated with these rearrangements in five malignant gliomas. In one tumor the rearrangement resulted in the deletion of most of the extracytoplasmic domain of the receptor, resulting in a hybrid mRNA between new sequences and the truncated EGFR sequence. The predicted amino acid sequence of the protein from this tumor was remarkably similar to that described for several viral erbB oncogenes. Four other tumors were noted to have internal deletions of the EGFR gene. These rearrangements brought about in-frame deletions affecting either of two cysteine-rich domains in the extracytoplasmic portion of the molecule. The clonal nature of these alterations, and the fact that identical alterations were seen in more than one tumor, suggests a role for these mutant receptor proteins in tumorigenesis. Further, these studies document the existence of tumor-specific cell surface molecules resulting from somatic mutation.

Full text

PDF
2965

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bigner S. H., Mark J., Bullard D. E., Mahaley M. S., Jr, Bigner D. D. Chromosomal evolution in malignant human gliomas starts with specific and usually numerical deviations. Cancer Genet Cytogenet. 1986 Jun;22(2):121–135. doi: 10.1016/0165-4608(86)90172-x. [DOI] [PubMed] [Google Scholar]
  2. Di Fiore P. P., Pierce J. H., Fleming T. P., Hazan R., Ullrich A., King C. R., Schlessinger J., Aaronson S. A. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell. 1987 Dec 24;51(6):1063–1070. doi: 10.1016/0092-8674(87)90592-7. [DOI] [PubMed] [Google Scholar]
  3. Downward J., Yarden Y., Mayes E., Scrace G., Totty N., Stockwell P., Ullrich A., Schlessinger J., Waterfield M. D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984 Feb 9;307(5951):521–527. doi: 10.1038/307521a0. [DOI] [PubMed] [Google Scholar]
  4. Gamett D. C., Tracy S. E., Robinson H. L. Differences in sequences encoding the carboxyl-terminal domain of the epidermal growth factor receptor correlate with differences in the disease potential of viral erbB genes. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6053–6057. doi: 10.1073/pnas.83.16.6053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  6. Haley J. D., Hsuan J. J., Waterfield M. D. Analysis of mammalian fibroblast transformation by normal and mutated human EGF receptors. Oncogene. 1989 Mar;4(3):273–283. [PubMed] [Google Scholar]
  7. Haley J., Whittle N., Bennet P., Kinchington D., Ullrich A., Waterfield M. The human EGF receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription. Oncogene Res. 1987 Sep-Oct;1(4):375–396. [PubMed] [Google Scholar]
  8. Humphrey P. A., Wong A. J., Vogelstein B., Friedman H. S., Werner M. H., Bigner D. D., Bigner S. H. Amplification and expression of the epidermal growth factor receptor gene in human glioma xenografts. Cancer Res. 1988 Apr 15;48(8):2231–2238. [PubMed] [Google Scholar]
  9. Humphrey P. A., Wong A. J., Vogelstein B., Zalutsky M. R., Fuller G. N., Archer G. E., Friedman H. S., Kwatra M. M., Bigner S. H., Bigner D. D. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4207–4211. doi: 10.1073/pnas.87.11.4207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ishii S., Xu Y. H., Stratton R. H., Roe B. A., Merlino G. T., Pastan I. Characterization and sequence of the promoter region of the human epidermal growth factor receptor gene. Proc Natl Acad Sci U S A. 1985 Aug;82(15):4920–4924. doi: 10.1073/pnas.82.15.4920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Janson C. H., Tehrani M. J., Mellstedt H., Wigzell H. Anti-idiotypic monoclonal antibody to a T-cell chronic lymphatic leukemia. Characterization of the antibody, in vitro effector functions and results of therapy. Cancer Immunol Immunother. 1989;28(3):225–232. doi: 10.1007/BF00204993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kris R. M., Lax I., Gullick W., Waterfield M. D., Ullrich A., Fridkin M., Schlessinger J. Antibodies against a synthetic peptide as a probe for the kinase activity of the avian EGF receptor and v-erbB protein. Cell. 1985 Mar;40(3):619–625. doi: 10.1016/0092-8674(85)90210-7. [DOI] [PubMed] [Google Scholar]
  14. Lax I., Burgess W. H., Bellot F., Ullrich A., Schlessinger J., Givol D. Localization of a major receptor-binding domain for epidermal growth factor by affinity labeling. Mol Cell Biol. 1988 Apr;8(4):1831–1834. doi: 10.1128/mcb.8.4.1831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Libermann T. A., Nusbaum H. R., Razon N., Kris R., Lax I., Soreq H., Whittle N., Waterfield M. D., Ullrich A., Schlessinger J. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985 Jan 10;313(5998):144–147. doi: 10.1038/313144a0. [DOI] [PubMed] [Google Scholar]
  16. Malden L. T., Novak U., Kaye A. H., Burgess A. W. Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res. 1988 May 15;48(10):2711–2714. [PubMed] [Google Scholar]
  17. Merlino G. T., Ishii S., Whang-Peng J., Knutsen T., Xu Y. H., Clark A. J., Stratton R. H., Wilson R. K., Ma D. P., Roe B. A. Structure and localization of genes encoding aberrant and normal epidermal growth factor receptor RNAs from A431 human carcinoma cells. Mol Cell Biol. 1985 Jul;5(7):1722–1734. doi: 10.1128/MCB.5.7.1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nistér M., Libermann T. A., Betsholtz C., Pettersson M., Claesson-Welsh L., Heldin C. H., Schlessinger J., Westermark B. Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res. 1988 Jul 15;48(14):3910–3918. [PubMed] [Google Scholar]
  19. Riedel H., Massoglia S., Schlessinger J., Ullrich A. Ligand activation of overexpressed epidermal growth factor receptors transforms NIH 3T3 mouse fibroblasts. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1477–1481. doi: 10.1073/pnas.85.5.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sugawa N., Ekstrand A. J., James C. D., Collins V. P. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8602–8606. doi: 10.1073/pnas.87.21.8602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
  22. Velu T. J., Beguinot L., Vass W. C., Willingham M. C., Merlino G. T., Pastan I., Lowy D. R. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene. Science. 1987 Dec 4;238(4832):1408–1410. doi: 10.1126/science.3500513. [DOI] [PubMed] [Google Scholar]
  23. Vogelstein B., Fearon E. R., Hamilton S. R., Preisinger A. C., Willard H. F., Michelson A. M., Riggs A. D., Orkin S. H. Clonal analysis using recombinant DNA probes from the X-chromosome. Cancer Res. 1987 Sep 15;47(18):4806–4813. [PubMed] [Google Scholar]
  24. Winship P. R. An improved method for directly sequencing PCR amplified material using dimethyl sulphoxide. Nucleic Acids Res. 1989 Feb 11;17(3):1266–1266. doi: 10.1093/nar/17.3.1266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Winter E., Yamamoto F., Almoguera C., Perucho M. A method to detect and characterize point mutations in transcribed genes: amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7575–7579. doi: 10.1073/pnas.82.22.7575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wong A. J., Bigner S. H., Bigner D. D., Kinzler K. W., Hamilton S. R., Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6899–6903. doi: 10.1073/pnas.84.19.6899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Xu Y. H., Ishii S., Clark A. J., Sullivan M., Wilson R. K., Ma D. P., Roe B. A., Merlino G. T., Pastan I. Human epidermal growth factor receptor cDNA is homologous to a variety of RNAs overproduced in A431 carcinoma cells. 1984 Jun 28-Jul 4Nature. 309(5971):806–810. doi: 10.1038/309806a0. [DOI] [PubMed] [Google Scholar]
  28. Yamazaki H., Fukui Y., Ueyama Y., Tamaoki N., Kawamoto T., Taniguchi S., Shibuya M. Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors. Mol Cell Biol. 1988 Apr;8(4):1816–1820. doi: 10.1128/mcb.8.4.1816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yamazaki H., Ohba Y., Tamaoki N., Shibuya M. A deletion mutation within the ligand binding domain is responsible for activation of epidermal growth factor receptor gene in human brain tumors. Jpn J Cancer Res. 1990 Aug;81(8):773–779. doi: 10.1111/j.1349-7006.1990.tb02644.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES