This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hermanson, M. Articles by Nistér, M. Search for Related Content PubMed PubMed Citation Articles by Hermanson, M. Articles by Nistér, M.

Association of Loss of Heterozygosity on Chromosome 17p with High Platelet-derived Growth Factor Receptor Expression in Human Malignant Gliomas¹

Ludwig Institute for Cancer Research, Biomedical Center, S-751 24, Uppsala [M. H., K. F., C-H. H.], and Department of Pathology, University Hospital, S-751 85, Uppsala [B. W., M. N.], Sweden; Department of Neuropathology, University of Bonn Medical Center, D-53105, Bonn, Germany [J. K., D. M., A. W., O. D. W., A. v. D.]; and Molecular Neuro-Oncology Laboratory, Neurosurgical Service, and Department of Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [D. N. L.]

The aim of this study was to examine platelet-derived growth factor receptor (PDGFR-) expression in gliomas of various degrees of malignancy and to correlate the findings with genetic alterations present in the same tumor samples. We analyzed 83 tumors by in situ hybridization using a PDGFR- cRNA probe. Increased PDGFR- mRNA expression was observed in astrocytic tumors of all stages of malignancy, although the highest levels were found in glioblastoma multiforme. To evaluate the frequency of PDGFR- gene amplification, differential PCR requiring less DNA than Southern analysis was used with fluorescence-labeled primers corresponding to the kinase insert region of the PDGFR-. Only 7 of 43 glioblastomas and none of the other tumors tested showed amplification of the PDGFR- gene, suggesting that a mechanism other than gene amplification is responsible for the overexpression of PDGFR- in glial brain tumors.

Comparison of the in situ hybridization data with genetic alterations in the same tumor material showed a significant correlation of loss of heterozygosity on chromosome 17p (Fisher's exact, P < 0.0002) with high expression levels of PDGFR-. Because that was the case in both low- and high-grade astrocytomas, our data imply that PDGFR- is actively involved in tumor cell proliferation in early and late stages of glioma development. The association of PDGFR- expression with a distinct subset of glioblastomas characterized by loss of heterozygosity 17p further supports the differentiation of these tumors into molecular variants.

¹ This work was supported in part by Swedish Cancer Foundation Grant 2999-B94-05XAC (M. N.), NIH Grant CA 57683 (D. N. L.), and Deutsch Forschungsgemeinschaft Grant SFB 400 (A. v. D., O. D. W.).

² To whom requests for reprints should be addressed. Phone: 46-18-66-38-45; Fax: 46-18-55-89-31.

Received 7/ 6/95. Accepted 10/24/95.

This article has been cited by other articles:

				E. Raymond, A. A. Brandes, C. Dittrich, P. Fumoleau, B. Coudert, P. M.J. Clement, M. Frenay, R. Rampling, R. Stupp, J. M. Kros, et al. Phase II Study of Imatinib in Patients With Recurrent Gliomas of Various Histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study J. Clin. Oncol., October 1, 2008; 26(28): 4659 - 4665. [Abstract] [Full Text] [PDF]

				J. Andrae, R. Gallini, and C. Betsholtz Role of platelet-derived growth factors in physiology and medicine Genes & Dev., May 15, 2008; 22(10): 1276 - 1312. [Abstract] [Full Text] [PDF]

				K. Twigger, L. Vidal, C. L. White, J. S. De Bono, S. Bhide, M. Coffey, B. Thompson, R. G. Vile, L. Heinemann, H. S. Pandha, et al. Enhanced In vitro and In vivo Cytotoxicity of Combined Reovirus and Radiotherapy Clin. Cancer Res., February 1, 2008; 14(3): 912 - 923. [Abstract] [Full Text] [PDF]

				N. Holtkamp, N. Ziegenhagen, E. Malzer, C. Hartmann, A. Giese, and A. von Deimling Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme Neuro-oncol, July 1, 2007; 9(3): 291 - 297. [Abstract] [Full Text] [PDF]

				S. S. M. Ng, Y.-T. Cheung, X.-M. An, Y. C. Chen, M. Li, G. Hoi-Yee Li, W. Cheung, J. Sze, L. Lai, Y. Peng, et al. Cell Cycle-Related Kinase: A Novel Candidate Oncogene in Human Glioblastoma J Natl Cancer Inst, June 20, 2007; 99(12): 936 - 948. [Abstract] [Full Text] [PDF]

				R. H. Alvarez, H. M. Kantarjian, and J. E. Cortes Biology of Platelet-Derived Growth Factor and Its Involvement in Disease Mayo Clin. Proc., September 1, 2006; 81(9): 1241 - 1257. [Abstract] [Full Text] [PDF]

				D. A. Reardon, J. N. Rich, H. S. Friedman, and D. D. Bigner Recent Advances in the Treatment of Malignant Astrocytoma J. Clin. Oncol., March 10, 2006; 24(8): 1253 - 1265. [Abstract] [Full Text] [PDF]

				N. Holtkamp, A. F. Okuducu, J. Mucha, A. Afanasieva, C. Hartmann, I. Atallah, L. Estevez-Schwarz, C. Mawrin, R. E. Friedrich, V.-F. Mautner, et al. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity Carcinogenesis, March 1, 2006; 27(3): 664 - 671. [Abstract] [Full Text] [PDF]

				V. Rand, J. Huang, T. Stockwell, S. Ferriera, O. Buzko, S. Levy, D. Busam, K. Li, J. B. Edwards, C. Eberhart, et al. Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas PNAS, October 4, 2005; 102(40): 14344 - 14349. [Abstract] [Full Text] [PDF]

				D. Ma, C. L. Nutt, P. Shanehsaz, X. Peng, D. N. Louis, and D. M. Kaetzel Autocrine Platelet-Derived Growth Factor-Dependent Gene Expression in Glioblastoma Cells Is Mediated Largely by Activation of the Transcription Factor Sterol Regulatory Element Binding Protein and Is Associated with Altered Genotype and Patient Survival in Human Brain Tumors Cancer Res., July 1, 2005; 65(13): 5523 - 5534. [Abstract] [Full Text] [PDF]

				W. G. Roberts, P. M. Whalen, E. Soderstrom, G. Moraski, J. P. Lyssikatos, H.-F. Wang, B. Cooper, D. A. Baker, D. Savage, D. Dalvie, et al. Antiangiogenic and Antitumor Activity of a Selective PDGFR Tyrosine Kinase Inhibitor, CP-673,451 Cancer Res., February 1, 2005; 65(3): 957 - 966. [Abstract] [Full Text] [PDF]

				C De Bustos, A Smits, B Stromberg, V P Collins, M Nister, and G Afink A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas J. Med. Genet., January 1, 2005; 42(1): 31 - 37. [Abstract] [Full Text] [PDF]

				S. J. Kim, H. Uehara, S. Yazici, R. R. Langley, J. He, R. Tsan, D. Fan, J. J. Killion, and I. J. Fidler Simultaneous Blockade of Platelet-Derived Growth Factor-Receptor and Epidermal Growth Factor-Receptor Signaling and Systemic Administration of Paclitaxel as Therapy for Human Prostate Cancer Metastasis in Bone of Nude Mice Cancer Res., June 15, 2004; 64(12): 4201 - 4208. [Abstract] [Full Text] [PDF]

				C. V. Ustach, M. E. Taube, N. J. Hurst Jr., S. Bhagat, R. D. Bonfil, M. L. Cher, L. Schuger, and H.-R. C. Kim A Potential Oncogenic Activity of Platelet-Derived Growth Factor D in Prostate Cancer Progression Cancer Res., March 1, 2004; 64(5): 1722 - 1729. [Abstract] [Full Text] [PDF]

				R. F. Hwang, K. Yokoi, C. D. Bucana, R. Tsan, J. J. Killion, D. B. Evans, and I. J. Fidler Inhibition of Platelet-Derived Growth Factor Receptor Phosphorylation by STI571 (Gleevec) Reduces Growth and Metastasis of Human Pancreatic Carcinoma in an Orthotopic Nude Mouse Model Clin. Cancer Res., December 15, 2003; 9(17): 6534 - 6544. [Abstract] [Full Text] [PDF]

				S. Godard, G. Getz, M. Delorenzi, P. Farmer, H. Kobayashi, I. Desbaillets, M. Nozaki, A.-C. Diserens, M.-F. Hamou, P.-Y. Dietrich, et al. Classification of Human Astrocytic Gliomas on the Basis of Gene Expression: A Correlated Group of Genes with Angiogenic Activity Emerges As a Strong Predictor of Subtypes Cancer Res., October 15, 2003; 63(20): 6613 - 6625. [Abstract] [Full Text] [PDF]

				R. V. Hoch and P. Soriano Roles of PDGF in animal development Development, October 15, 2003; 130(20): 4769 - 4784. [Abstract] [Full Text] [PDF]

				G. Hesselager, L. Uhrbom, B. Westermark, and M. Nister Complementary Effects of Platelet-derived Growth Factor Autocrine Stimulation and p53 or Ink4a-Arf Deletion in a Mouse Glioma Model Cancer Res., August 1, 2003; 63(15): 4305 - 4309. [Abstract] [Full Text] [PDF]

				A. Perry Pathology of low-grade gliomas: An update of emerging concepts Neuro-oncol, July 1, 2003; 5(3): 168 - 178. [Abstract] [PDF]

				D Ribom, J Andrae, M Frielingsdorf, M Hartman, M Nister, and A Smits Prognostic value of platelet derived growth factor {alpha} receptor expression in grade 2 astrocytomas and oligoastrocytomas J. Neurol. Neurosurg. Psychiatry, June 1, 2002; 72(6): 782 - 787. [Abstract] [Full Text] [PDF]

				E. J. Baxter, A. Hochhaus, P. Bolufer, A. Reiter, J. M. Fernandez, L. Senent, J. Cervera, F. Moscardo, M. A. Sanz, and N. C.P. Cross The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA Hum. Mol. Genet., June 1, 2002; 11(12): 1391 - 1397. [Abstract] [Full Text] [PDF]

				C. Dai, J. C. Celestino, Y. Okada, D. N. Louis, G. N. Fuller, and E. C. Holland PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo Genes & Dev., August 1, 2001; 15(15): 1913 - 1925. [Abstract] [Full Text] [PDF]

				E. A. Maher, F. B. Furnari, R. M. Bachoo, D. H. Rowitch, D. N. Louis, W. K. Cavenee, and R. A. DePinho Malignant glioma: genetics and biology of a grave matter Genes & Dev., June 1, 2001; 15(11): 1311 - 1333. [Full Text] [PDF]

				J. M. MARKERT, C. M. FULLER, G. Y. GILLESPIE, J. K. BUBIEN, L. A. MCLEAN, R. L. HONG, K. LEE, S. R. GULLANS, T. B. MAPSTONE, and D. J. BENOS Differential gene expression profiling in human brain tumors Physiol Genomics, February 7, 2001; 5(1): 21 - 33. [Abstract] [Full Text] [PDF]

				L. M. DeAngelis Brain Tumors N. Engl. J. Med., January 11, 2001; 344(2): 114 - 123. [Full Text] [PDF]

				H. Huang, S. Colella, M. Kurrer, Y. Yonekawa, P. Kleihues, and H. Ohgaki Gene Expression Profiling of Low-Grade Diffuse Astrocytomas by cDNA Arrays Cancer Res., December 1, 2000; 60(24): 6868 - 6874. [Abstract] [Full Text]

				T. Kilic, J. A. Alberta, P. R. Zdunek, M. Acar, P. Iannarelli, T. O’Reilly, E. Buchdunger, P. M. Black, and C. D. Stiles Intracranial Inhibition of Platelet-derived Growth Factor-mediated Glioblastoma Cell Growth by an Orally Active Kinase Inhibitor of the 2-Phenylaminopyrimidine Class Cancer Res., September 1, 2000; 60(18): 5143 - 5150. [Abstract] [Full Text]

				P. Kleihues and H. Ohgaki Phenotype vs Genotype in the Evolution of Astrocytic Brain Tumors Toxicol Pathol, January 1, 2000; 28(1): 164 - 170. [Abstract] [PDF]

				C.-H. Heldin and B. Westermark Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor Physiol Rev, October 1, 1999; 79(4): 1283 - 1316. [Abstract] [Full Text] [PDF]

				Y. Shoshan, A. Nishiyama, A. Chang, S. Mork, G. H. Barnett, J. K. Cowell, B. D. Trapp, and S. M. Staugaitis Expression of oligodendrocyte progenitor cell antigens by gliomas: Implications for the histogenesis of brain tumors PNAS, August 31, 1999; 96(18): 10361 - 10366. [Abstract] [Full Text] [PDF]

				O. Bögler, M. Nagane, J. Gillis, H-J. Su Huang, and W. K. Cavenee Malignant Transformation of p53-deficient Astrocytes Is Modulated by Environmental Cues in Vitro Cell Growth Differ., February 1, 1999; 10(2): 73 - 86. [Abstract] [Full Text]

				P. Kleihues and H. Ohgaki Primary and secondary glioblastomas: From concept to clinical diagnosis Neuro-oncol, January 1, 1999; 1(1): 44 - 51. [Abstract] [PDF]

				J. W. Mandell, I. M. Hussaini, M. Zecevic, M. J. Weber, and S. R. VandenBerg In Situ Visualization of Intratumor Growth Factor Signaling : Immunohistochemical Localization of Activated ERK/MAP Kinase in Glial Neoplasms Am. J. Pathol., November 1, 1998; 153(5): 1411 - 1423. [Abstract] [Full Text] [PDF]