Comparative genomic in situ hybridization discloses recurrent gain of chromosome 4 in experimental gliomas of the rat

The genetic characterization of experimental tumors is essential in order to evaluate their relevance as appropriate animal models for human neoplasms. We have used flow cytometry and a recently established Comparative Genomic in situ Hybridization (CGH) protocol for the rat (Kappler et al., 1998) to investigate chromosome copy number changes in five ethylnitrosourea induced gliomas of the rat. Flow cytometry showed aneuploid DNA indices in three of the tumors investigated. CGH analysis of primary tumors revealed whole chromosome and subchromosomal gains of rat chromosomes (RNO) 1, 2, 4, 6, 7, 10, 11, 12, and 13. Loss of RNO 5q23→q35 was apparent in one tumor. High level copy number gains were not observed using CGH as well as semiquantitative PCR with Tgfa, Met and Hbb primers. Low copy number gain of RNO 4 represents the most common aberration, since it was detected in four of five tumors investigated. Three tumors showed gain of RNO 7, while two tumors showed gains of RNO 10q31→qter and RNO 12q. Deletion of RNO 5q23→q35 and gain of RNO 4 occurred mutually exclusively. Therefore, we conclude that these two alterations may represent different pathways in the pathogenesis of experimental gliomas in the rat. Findings are discussed in analogy to human gliomas.

[1]  H. Scherthan,et al.  Chromosomal imbalances and DNA amplifications in SV40 large T antigen-induced primitive neuroectodermal tumor cell lines of the rat. , 1999, Carcinogenesis.

[2]  C. Szpirer,et al.  Assignment1 of the cyclin-dependent kinase inhibitor genes Cdkn2a and Cdkn2b to rat chromosome bands 5q32→q34 and 5q31→q33, respectively by fluorescence in situ hybridization, using small PCR-generated probes , 1998, Cytogenetic and Genome Research.

[3]  G. Evan,et al.  Traps to catch unwary oncogenes. , 1998, Trends in genetics : TIG.

[4]  E. Hudson,et al.  Met and hepatocyte growth factor/scatter factor expression in human gliomas. , 1997, Cancer research.

[5]  T. Bayer,et al.  Characterization of Neural Cell Lines Derived from SV40 Large T‐Induced Primitive Neuroectodermal Tumors , 1997, Brain pathology.

[6]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[7]  C. Sommer,et al.  Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. , 1996, Oncogene.

[8]  L. Dworkin,et al.  Primary structure of rat HGF receptor and induced expression in glomerular mesangial cells. , 1996, The American journal of physiology.

[9]  E. Schröck,et al.  Recurrent gain of chromosome arm 7q in low‐grade astrocytic tumors studied by comparative genomic hybridization , 1996, Genes, chromosomes & cancer.

[10]  H. Scherthan,et al.  Detection of Complex Genetic Alterations in Human Glioblastoma Multiforme Using Comparative Genomic Hybridization , 1996, Journal of neuropathology and experimental neurology.

[11]  F. Mitelman.  ISCN 1995 : an international system for human cytogenetic nomenclature (1995) : recommendations of the International Standing Committee on Human Cytogenetic Nomenclature : Memphis, Tennessee, USA, October 9-13, 1994 , 1995 .

[12]  H. Tsubouchi,et al.  Concomitant expression of hepatocyte growth factor (HGF), HGF activator and c‐met genes in human glioma cells in vitro , 1995, FEBS letters.

[13]  G. Hannon,et al.  Cloning and characterization of murine p16INK4a and p15INK4b genes. , 1995, Oncogene.

[14]  J. Herman,et al.  5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers , 1995, Nature Medicine.

[15]  J Piper,et al.  Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors , 1994, Genes, chromosomes & cancer.

[16]  D. Pinkel,et al.  Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors , 2022 .

[17]  G. Levan,et al.  The gene map of the Norway rat (Rattus norvegicus) and comparative mapping with mouse and man. , 1991, Genomics.

[18]  J. Azizkhan,et al.  Characterization of the rat transforming growth factor alpha gene and identification of promoter sequences , 1990, Molecular and cellular biology.

[19]  L. Cheng,et al.  Genomic sequence of a Sprague - Dawley rat β-globin gene , 1988 .

[20]  S. Soukup,et al.  Association of chromosome 4 abnormalities with ethylnitrosourea-induced neuro-oncogenesis in the rat. , 1984, Cancer research.

[21]  G. Klein,et al.  Rat c-myc oncogene is located on chromosome 7 and rearranges in immunocytomas with t(6:7) chromosomal translocation , 1983, Nature.

[22]  T. Mandybur,et al.  Excess chromosome no. 4 in ethylnitrosourea-induced neurogenic tumor lines of the rat. , 1977, Journal of the National Cancer Institute.

[23]  Fredrik Ståhl,et al.  The RATMAP database , 1995 .

[24]  G. Hannon,et al.  Cloning and characterization of murine p16(INK4a) and p15(INK4b) genes , 1995 .

[25]  A. Jauch,et al.  Copyright ©) American Society for Investigative Pathology Comparative Genomic Hybridization of Human Malignant Gliomas Reveals Multiple Amplification Sites and Nonrandom Chromosomal Gains and Losses , 2022 .

[26]  W. Yung,et al.  Differental amplification of the TGF-α gene in human gliomas , 1990 .

[27]  Iscn.  International System for Human Cytogenetic Nomenclature , 1978 .