Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16INK4a deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C→A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter (∼70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.

/pdf/genetic-pathways-to-primary-and-secondary-glioblastoma-54aazofmor.pdf

Genetic Pathways to Primary and Secondary Glioblastoma

A database of DNA fingerprint profiles from permanently established human and animal cell lines was prepared with a computer program originally designed for numerical taxonomy of bacteria. Identifications of cell line DNA profiles were performed, both by the Pearson product-moment correlation coefficient and by band matching. Under the conditions used the Pearson product-moment correlation coefficient was consistently more reliable.

The Pearson product‐moment correlation coefficient is better suited for identification of DNA fingerprint profiles than band matching algorithms

Nine human malignant gliomas (2 astrocytomas grade III and 7 glioblastomas) were analyzed using comparative genomic hybridization (CGH). In addition to the amplification of the EGFR gene at 7p12 in 4 of 9 cases, six new amplification sites were mapped to 1q32, 4q12, 7q21.1, 7q21.2-3, 12p, and 22q12. Nonrandom chromosomal gains and losses were identified with overrepresentation of chromosome 7 and underrepresentation of chromosome 10 as the most frequent events (1 of 2 astrocytomas, 7 of 7 glioblastomas). Gain of a part or the whole chromosome 19 and losses of chromosome bands 9pter-23 and 22q13 were detected each in five cases. Loss of chromosome band 17p13 and gain of chromosome 20 were revealed each in three cases. The validity of the CGH data was confirmed using interphase cytogenetics with YAC clones, chromosome painting in tumor metaphase spreads, and DNA fingerprinting. A comparison of CGH data with the results of chromosome banding analyses indicates that metaphase spreads accessible in primary tumor cell cultures may not represent the clones predominant in the tumor tissue.

https://epub.ub.uni-muenchen.de/9395/1/cremer_thomas_9395.pdf

Comparative genomic hybridization of human malignant gliomas reveals multiple amplification sites and nonrandom chromosomal gains and losses.

A panel of simple repetitive oligonucleotide probes has been designed and tested for multilocus DNA fingerprinting in some 200 fungal, plant and animal species as well as man. To date at least one of the probes has been found to be informative in each species. The human genome, however, has been the major target of many fingerprinting studies. Using the probe (CAC)5 or (GTG)5, individualization of all humans is possible except for monozygotic twins. Paternity analyses are now performed on a routine basis by the use of multilocus fingerprints, including also cases of deficiency, i.e. where one of the parents is not available for analysis. In forensic science stain analysis is feasible in all tissue remains containing nucleated cells. Depending on the degree of DNA degradation a variety of oligonucleotides are informative, and they have been proven useful in actual case work. Advantages in comparison to other methods including enzymatic DNA amplification techniques (PCR) are evident. Fingerprint patterns of tumors may be changed due to the gain or loss of chromosomes and/or intrachromosomal deletion and amplification events. Locus-specific probes were isolated from the human (CAC)5/(GTG)5 fingerprint with a varying degree of informativeness (monomorphic versus truly hypervariable markers). The feasibility of three different approaches for the isolation of hypervariable mono-locus probes was evaluated. Finally, one particular mixed simple (gt)n(ga)m repeat locus in the second intron of the HLA-DRB genes has been scrutinized to allow comparison of the extent of exon-encoded (protein-) polymorphisms versus intronic hypervariability of simple repeats: adjacent to a single gene sequence (e.g. HLA-DRB1*0401) many different length alleles were found. Group-specific structures of basic repeats were identified within the evolutionarily related DRB alleles. As a further application it is suggested here that due to the ubiquitous interspersion of their targets, short probes for simple repeat sequences are especially useful tools for ordering genomic cosmid, yeast artificial chromosome and phage banks.

/pdf/oligonucleotide-fingerprinting-using-simple-repeat-motifs-a-3wo0aadvdj.pdf

Oligonucleotide fingerprinting using simple repeat motifs: a convenient, ubiquitously applicable method to detect hypervariability for multiple purposes.

Consistent tumor-specific chromosomal aberrations have not been described in low-grade astrocytic tumors. The most frequent genetic alterations are mutations of the TP53 tumor suppressor gene and/or loss of heterozygosity (LOH) on 17p that occur in about 30% of the cases in adult patients but that are uncommon in childhood tumors. We used comparative genomic hybridization (CGH) to map DNA copy number alterations in 18 primary low-grade astrocytic tumors (ten adult patients and eight children). A gain of chromosome arm 7q was the most frequent event detected in five of ten astrocytomas (50%) from adult patients, followed by DNA amplification on chromosome arm 8q and gain on 12p (two cases). Loss of chromosomal regions on 1p, 4q, and the X chromosome was observed in two of ten cases [including one patient afflicted with Turner syndrome (45,X)]. In contrast, no consistent changes were observed in low-grade astrocytomas in children. A loss of the X chromosome was the sole aberration detected in two of eight cases using DNA extracted from the normal brain tissue. The findings suggest that a gain of 7q is an early event in the initiation of astrocytomas in adult patients. The discrepant findings in low-grade astrocytic tumors in adults compared to tumors in children support the the hypothesis that there might be different mechanisms responsible for tumor development.

Recurrent gain of chromosome arm 7q in low-grade astrocytic tumors studied by comparative genomic hybridization.

DNA fingerprints were generated by the oligonucleotide probe (GTG)5 from surgically removed tissue and/or primary cell culture of 36 intracranial tumors (31 gliomas, 1 medulloblastoma, 4 metastatic carcinomas) and compared with the constitutional banding pattern obtained from the peripheral blood leukocytes of each patient. A multitude of somatic changes was detected and found to reflect the chromosome alterations identified by parallel karyotype analysis. Gain and/or loss of bands or significant band intensity shifts could be demonstrated in the fingerprints of more than 80% of the tumors investigated. This included a highly amplified fingerprint fragment in five independent gliomas (four of them had double minutes, dmin) which appeared not individual- but tumor-specific (2.4 kilobases, kb, after HaeIII digestion). Rehybridization with the oligonucleotide probes (GT)8 and (GATA)4, respectively, revealed additional amplified fingerprint fragments in the tumor DNA of these patients. While a (ca/gt)n fragment (2.6 kb. HaeIII) was also found to be amplified in all five cases, one band detected with (GATA)4 (1.4 kb, HaeIII) represented a unique feature for one of these tumors only. Amplification of the epidermal growth factor receptor (EGFR) gene via Southern blot hybridization was revealed only in those tumors showing the amplified DNA fingerprint fragments as well. Thus in many gliomas the amplification unit harbors two simple repetitive DNA fingerprint loci, (cac/gtg)n and (ca/gt)n, in addition to the EGFR gene.

Coamplification of simple repetitive DNA fingerprint fragments and the EGFR gene in human gliomas.

Germline and somatic instability of the human genome was studied, using synthetic oligonucleotides specific for simple repeat motifs. The following probes were used: (GTG)5, (GACA)4, (GATA)4, (CT)8, (TTAGGG)3, (GT)8, (GAA)6 and (GGAT)4. Each of them is unique with respect to the target regions recognized in the genome. Thus compilation of the various fingerprint data provides a complex map of the genome (and its deviations). While the fingerprints of differentiated somatic tissues never showed any alterations, in tumor tissues (namely gliomas) many changes could be detected. Most of the latter reflect secondary karyological aberrations. In nearly one third of the gliomas, drastically amplified and apparently monomorphic DNA fragments were identified. This marker should make it possible to deal with causal pathogenetic mechanisms as well as novel diagnostic strategies.

Monitoring genomic alterations with a panel of oligonucleotide probes specific for various simple repeat motifs.

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Coamplification of simple repetitive DNA fingerprint fragments and the EGFR gene in human gliomas.

Monitoring genomic alterations with a panel of oligonucleotide probes specific for various simple repeat motifs.