Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Report
  • Published:

p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma

Abstract

P16 and P14ARF are two tumor suppressors encoded by the locus ink4a-arf which is frequently deleted in human tumors. Recent experiments performed with mouse embryonic fibroblasts have shown that P14ARF is an upstream regulator of the P53 pathway. This raises the question as to whether in human tumors the loss of p14arf and mutation of p53 are mutually exclusive events which segregate with genetic alterations at other loci. To examine this question we performed a multigenic analysis on 29 gliomas. We analysed p53 and p14arf in relation with five other genetic loci encoding the most frequently mutated genes in human gliomas: cdkn2a, mdm2, egfr, pten and the chromosomal regions 10q23.3 and 10q25-26. Our study shows for the first time that p53 mutations and p14arf deletions appear mutually exclusive in human glioblastoma, suggesting that they may be functionally redundant in glioma tumorigenesis. The P53 pathway is, therefore, disrupted in 81.8% of malignant gliomas (WHO grades III and IV), either by mutation of the p53 gene (31.8%) or by p14arf deletion (54.5%). These tumors further showed MDM2 overexpression (9.1%), egfr oncogene amplification/egfr overexpression (50%), pten mutations (27.3%) and loss of heterozygosity (LOH) at the chromosomal regions 10q23.3 (86.4%) and 10q25-26 (100%). These alterations did not segregate with p53 mutations or p14arf deletions, while p14arf and cdkn2a were always deleted.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Biernat W, Kleihues P, Yonekawa Y and Ohgaki H. . 1997a Neuropathol. Exp. Neurol. 56: 180–185.

  • Biernat W, Tohma Y, Yonekawa Y, Kleihues P and Ohgaki H. . 1997b Acta. Neuropathol. (Berl.) 94: 303–309.

  • Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W et al. 1995 Nat. Genet. 11: 210–212.

  • Chiariello E, Roz L, Albarosa R, Magnani I and Finocchiaro G. . 1998 Oncogene 16: 541–545.

  • Costello JF, Plass C, Arap W, Chapman VM, Held WA, Berger MS, Huang HJS and Cavenee WK. . 1997 Cancer Res. 57: 1250–1254.

  • de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ and Lowe SW. . 1998 Genes Dev. 12: 2434–2442.

  • Duerr EM Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, Schramm J, Wiestler OD, Parsons R, Eng C and von Deimling A. . 1998 Oncogene 16: 2259–2264.

  • Duro D, Bernard O, Della Valle V, Berger R and Larsen CJ. . 1995 Oncogene 11: 21–29.

  • Frye RA, Benz CC and Liu E. . 1989 Oncogene 4: 1153–1157.

  • Fueyo J, Gomez-Manzano C, Yung WK and Kyritsis AP. . 1998 Neurology 51: 1250–1255.

  • Fulci G, Ishii N and Van Meir EG. . 1998 Brain Pathol. 8: 599–613.

  • Gazzeri S, Della Valle V, Chaussade L, Brambilla C, Larsen CJ and Brambilla E. . 1998 Cancer Res. 58: 3926–3931.

  • Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao ZX, Kumar S, Howley PM and Livingston DM. . 1998 Mol. Cell 2: 405–415.

  • Hayashi Y, Ueki K, Waha A, Wiestler OD, Louis DN and von Deimling A. . 1997 Brain Pathol. 7: 871–875.

  • He J, Allen JR, Collins VP, Allalunis-Turner MJ, Godbout R, Day RS, III and James CD. . 1994 Cancer Res. 54: 5804–5807.

  • Hegi ME, zur Hausen A, Ruedi D, Malin G and Kleihues P. . 1997 Int. J. Cancer 73: 57–63.

  • Honda R and Yasuda H. . 1999 EMBO J. 18: 22–27.

  • Hunter SB, Abbott K, Varma VA, Olson JJ, Barnett DW and James CD. . 1995 J. Neuropathol. Exp. Neurol. 54: 57–64.

  • Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A and Collins VP. . 2000 Cancer Res. 60: 417–424.

  • Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW and Vogelstein B. . 1994 Cancer Res. 54: 6353–6358.

  • Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J et al. 1994 Nat. Genet. 8: 23–26.

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G and Sherr CJ. . 1997 Cell 91: 649–659.

  • Kleihues P, Ohgaki H, Eibl RH, Reichel MB, Mariani L, Gehring M, Petersen I, Holl T, von Deimling A, Wiestler OD, et al. 1994 Recent Results Cancer Res. 135: 25–31.

  • Landers JE, Haines DS, Strauss JF, III and George DL. . 1994 Oncogene 9: 2745–2750.

  • Maddalena AS, Hainfellner JA, Hegi ME, Glatzel M and Aguzzi A. . 1999 Brain Pathol. 9: 627–637.

  • Maier D, Comparone D, Taylor E, Zhang Z, Gratzl O, Van Meir EG, Scott RJ and Merlo A. . 1997 Oncogene 15: 997–1000.

  • Maier D, Zhang Z, Taylor E, Hamou MF, Gratzl O, Van Meir EG, Scott RJ and Merlo A. . 1998 Oncogene 16: 3331–3335.

  • Mao L, Merlo A, Bedi G, Shapiro GI, Edwards CD, Rollins BJ and Sidransky D. . 1995 Cancer Res. 55: 2995–2997.

  • Meyer-Puttlitz B, Hayashi Y, Waha A, Rollbrocker B, Bostrom J, Wiestler OD, Louis DN, Reifenberger G and von Deimling A. . 1997 Am. J. Pathol. 151: 853–857.

  • Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A and Poustka A. . 1997 Nat. Genet. 17: 32–39.

  • Nakamura H, Yoshida M, Tsuiki H, Ito K, Ueno M, Nakao M, Oka K, Tada M, Kochi M, Kuratsu J, Ushio Y and Saya H. . 1998 Oncogene 16: 1009–1019.

  • Nishikawa R, Furnari FB, Lin H, Arap W, Berger MS, Cavenee WK and Huang HJS. . 1995 Cancer Res. 55: 1941–1945.

  • Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK and Huang HJS. . 1994 Proc. Natl. Acad. Sci. USA 91: 7727–7731.

  • Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW and Vogelstein B. . 1993 Nature 362: 857–860.

  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C and DePinho RA. . 1998 Cell 92: 713–723.

  • Reifenberger G, Liu L, Ichimura K, Schmidt EE and Collins VP. . 1993 Cancer Res. 53: 2736–2739.

  • Sanchez-Cespedes M, Reed AL, Buta M, Wu L, Westra WH, Herman JG, Yang SC, Jen J and Sidransky D. . 1999 Oncogene 18: 5843–5849.

  • Schmidt EE, Ichimura K, Reifenberger G and Collins VP. . 1994 Cancer Res. 54: 6321–6324.

  • Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G and Kamb A. . 1995 Cancer Res. 55: 2988–2994.

  • Sure U, Ruedi D, Tachibana O, Yonekawa Y, Ohgaki H, Kleihues P and Hegi ME. . 1997 J. Neuropathol. Exp. Neurol. 56: 782–789.

  • Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P, Yung WK, Fujii G, Berson A, Steck PA et al. 1997 Cancer Res. 57: 5221–5225.

  • von Deimling A, Louis DN and Wiestler OD. . 1995 Glia 15: 328–338.

  • Vonlanthen S, Heighway J, Tschan MP, Borner MM, Altermatt HJ, Kappeler A, Tobler A, Fey MF, Thatcher N, Yarbrough WG and Betticher DC. . 1998 Oncogene 17: 2779–2785.

  • Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D and Parsons R. . 1997 Cancer Res. 57: 4183–4186.

  • Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P, Frebourg T and Iggo R. . 1997 Oncogene 14: 163–169.

  • Xiao ZX, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR and Livingston DM. . 1995 Nature 375: 694–698.

  • Zhang Y and Xiong Y. . 1999 Mol. Cell 3: 579–591.

  • Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ and Roussel MF. . 1998 Genes Dev. 12: 2424–2433.

Download references

Acknowledgements

We would like to thank N de Tribolet for support and encouragement, A Aguzzi for providing us positive controls for immunohistochemistry, H-JS Huang for giving us the mutant EGFRT-cDNA that was used to make the positive control for the detection of the truncated form of EGFR and Solange Gros for helping in the performance of the IHC staining. Moreover we would like to thank R Iggo for providing us the kit for the p53 functional assay in yeast, N de Tribolet, PY Dietrich, M-F Hamou and the neurosurgical staff of the University Hospitals of Lausanne, Basel and Geneva for providing tumor samples. This work was supported by MBNA, N.A. (to the Laboratory of Molecular Neuro-Oncology), and by the following grants: Swiss National Science Foundation 4037-044729 and 31-49194.96 (to EG Van Meir), Swiss Cancer Research Foundation KFS 172-9-1995 (to EG Van Meir), Swiss Cancer League KFS-6/4-2-1998 (to A Merlo) and NAFO 31-053746.98 (to A Merlo).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fulci, G., Labuhn, M., Maier, D. et al. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 19, 3816–3822 (2000). https://doi.org/10.1038/sj.onc.1203700

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203700

Keywords

This article is cited by

Search

Quick links