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Deletion and tandem duplication of exons 2–7 in the epidermal growth factor receptor gene of a human malignant glioma

Oncogene volume 19, pages 4542–4548 (2000)Cite this article

Abstract

The epidermal growth factor receptor (EGFR) gene is frequently amplified and rearranged in malignant gliomas with expression of oncogenic deletion mutants (DM). The most common mutant EGFRvIII, which contains a deletion of exons 2–7, is constitutively autophosphorylated and inefficiently downregulated. Other less common EGFR mRNA species in gliomas contain tandem duplication of exons, which encode the tyrosine kinase (TK) and calcium mediated receptor internalization (CAIN) domains of the molecule. We examined a panel of human malignant gliomas and found one tumor that expressed four related EGFR proteins, including 125-, 140-, 170-, and 180-kDa species. This tumor also contained four EGFR-related mRNA species, including both wild type EGFR and EGFRvIII transcripts. A third transcript contained a deletion of exons 2–7 and 12–13 corresponding to the 125-kDa protein. A fourth transcript contained an in-frame, tandem duplication of exons 2–7 (EGFR.TDM/2–7). The 180-kDa, tandem duplication mutant (TDM) exhibited enhanced basal phosphorylation and impaired downregulation. In contrast to the 140-kDa EGFRvIII; however, phosphorylation of the 180-kDa EGFR.TDM/2–7 was strongly induced by ligand. Expression of both deletion and tandem duplication mutants in the same tumor suggests that the mechanisms responsible for DM and TDM formation might be closely related.

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References

  • Aoki T, Tashiro K, Miyatake S-, Nakano T, Oda Y, Kikuchi H and Honjo T. . 1991 Biochem. Biophys. Res. Comm. 181: 151–158.

  • Bailin T, Mo X and Sadofsky MJ. . 1999 Mol. Cell. Biol. 19: 4664–4671.

  • Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS and Bigner DD. . 1995 Cell Growth Diff. 6: 1251–1259.

  • Bigner SH, Humphrey PA, Wong AJ, Vogelstein B, Mark J, Friedman HS and Bigner DD. . 1990 Cancer Res. 50: 8017–8022.

  • Blasband AJ, Gilligan DM, Winchell LF, Wong ST, Luetteke NC, Rogers KT and Lee DC. . 1990 Oncogene 5: 1213–1221.

  • Callaghan T, Anctczak M, Flickinger T, Raines M, Myers M and Kung H-J. . 1993 Oncogene 8: 2939–2948.

  • Chu CT, Everiss KD, Wikstrand CJ, Batra SK, Kung H-J and Bigner DD. . 1997 Biochem. J. 324: 855–861.

  • Chun JJM, Schatz DG, Oettinger MA, Jaenisch R and Baltimore D. . 1991 Cell 64: 189–200.

  • Ciesielski MJ and Fenstermaker RA. . 2000 Oncogene 19: 810–820.

  • Di Fiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR, Schlessinger J and Aaronson SA. . 1987 Cell 51: 1063–1070.

  • Ekstrand AJ, James CD, Cavenee WK, Seliger B, Petterson RF and Collins VP. . 1991 Cancer Res. 51: 2164–2172.

  • Fenstermaker RA, Ciesielski MJ and Castiglia GJ. . 1998 Oncogene 16: 3435–3443.

  • Frederick L, Eley G, Wang X-Y and Jones CD. . 2000 Cancer Res. 60: 1383–1387.

  • Frisa PS, Walter EI, Ling L, Kung H-J and Jacobberger JW. . 1996 Cell Growth Differ. 7: 223–233.

  • Hiom K, Melek M and Gellert M. . 1998 Cell 94: 463–470.

  • Huang H-J, Su Nagane M, Klingbeil K, Lin H, Nishikawa R, Xiang-Dong J, Huang C-M, Gill GN, Wiley HS and Cavenee WK. . 1997 J. Biol. Chem. 272: 2927–2935.

  • Humphrey PA, Wong AJ, Vogelstein B, Friedman HS, Werner MH, Bigner DD and Bigner SH. . 1988 Cancer Res. 48: 2231–2238.

  • Humphrey PA, Gangarosa LM, Wong AJ, Archer GE, Lund-Johansen M, Bjerkvig R, Laerum O-D, Friedman HS and Bigner DD. . 1991 Biochem. Biophys. Res. Comm. 178: 1413–1420.

  • Le Beau MM and Rowley JD. . 1986 Adv. Hum. Genet. 15: 1–54.

  • Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A and Schlessinger J. . 1985 Nature (Lond.) 313: 144–147.

  • Maruno M, Kovach JS, Kelly PJ and Yanagihara T. . 1991 J. Neurosurg. 75: 97–102.

  • Montgomery RB, Moscatello DK, Wong AJ, Cooper JA and Stahl WL. . 1995 J. Biol. Chem. 270: 30562–30566.

  • Moscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY and Wong AJ. . 1996 Oncogene 13: 85–96.

  • Nagane M, Coufal F, Lin H, Bogler O, Cavenee WK, Huang H-J. . 1996 Cancer Res. 56: 5079–5086.

  • Nagane M, Levitzki A, Gazit A, Cavenee WK and Huang HJ. . 1998 Proc. Natl. Acad. Sci. USA 95: 5724–5729.

  • Nishikawa R, Xiang-Dong J, Harmon RC, Lazar CS, Gill GN, Cavenee WK and Huang HJ. . 1994 Proc. Natl. Acad. Sci. USA 91: 7727–7731.

  • Panneerselvam K, Kanakaraj P, Raj S, Das M and Bishayee S. . 1995 Eur. J. Biochem. 230: 951–957.

  • Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N and Kiessling M. . 1994 Int. J. Cancer 56: 72–77.

  • Steck PA, Lee P, Hung M-C and Yung WKA. . 1988 Cancer Res. 48: 5433–5439.

  • Sugawa N, Ekstrand AJ, James CD and Collins VP. . 1990 Proc. Natl. Acad. Sci. USA 87: 8602–8606.

  • Tashiro S, Kotomura N, Tanaka K, Suzuki K, Kyo T, Dohy H, Niwa O and Kamada N. . 1994 Oncogene 9: 1939–1945.

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD and Seeburg PH. . 1984 Nature (Lond.) 309: 418–425.

  • Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN and Rosenfeld MG. . 1990 Science 247: 962–964.

  • Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR and Vogelstein B. . 1987 Proc. Natl. Acad. Sci. USA 84: 6899–6903.

  • Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS and Vogelstein B. . 1992 Proc. Natl. Acad. Sci. USA 89: 2965–2969.

  • Wyatt RT, Rudders RA, Zelentz A, Delellis RA and Krontiris TG. . 1992 J. Exp. Med. 175: 1575–1588.

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Acknowledgements

This project was supported by NIH grant CA 16056-22, the Troup Foundation and the Jeffrey Wright Fund.

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Authors and Affiliations

  1. Department of Neurosurgery, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, 14209, NY, USA

    Robert A Fenstermaker

  2. Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, 14263, NY, USA

    Robert A Fenstermaker & Michael J Ciesielski

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Fenstermaker, R., Ciesielski, M. Deletion and tandem duplication of exons 2–7 in the epidermal growth factor receptor gene of a human malignant glioma. Oncogene 19, 4542–4548 (2000). https://doi.org/10.1038/sj.onc.1203802

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