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Molecular Cytogenetic Analysis in the Study of Brain Tumors: Findings and Applications

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Molecular Cytogenetic Analysis in the Study of Brain Tumors: Findings and Applications Neurosurg Focus 19 (5):E1, 2005 Molecular cytogenetic analysis in the study of brain tumors: findings and applications JANE BAYANI, M.H.SC., AJAY PANDITA, D.V.M., PH.D., AND JEREMY A. SQUIRE, PH.D. Department of Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network; Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children; and Departments of Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Ontario, Canada Classic cytogenetics has evolved from black and white to technicolor images of chromosomes as a result of advances in fluorescence in situ hybridization (FISH) techniques, and is now called molecular cytogenetics. Improvements in the quality and diversity of probes suitable for FISH, coupled with advances in computerized image analysis, now permit the genome or tissue of interest to be analyzed in detail on a glass slide. It is evident that the growing list of options for cytogenetic analysis has improved the understanding of chromosomal changes in disease initiation, progression, and response to treatment. The contributions of classic and molecular cytogenetics to the study of brain tumors have pro- vided scientists and clinicians alike with new avenues for investigation. In this review the authors summarize the con- tributions of molecular cytogenetics to the study of brain tumors, encompassing the findings of classic cytogenetics, interphase- and metaphase-based FISH studies, spectral karyotyping, and metaphase- and array-based comparative genomic hybridization. In addition, this review also details the role of molecular cytogenetic techniques in other aspects of understanding the pathogenesis of brain tumors, including xenograft, cancer stem cell, and telomere length studies. KEY WORDS • fluorescence in situ hybridization • comparative genomic hybridization • spectral karyotyping • chromosome • microarray • gene amplification A BRIEF HISTORY OF HUMAN combined the disciplines of cytology and genetics to coin CYTOGENETICS the term cytogenetics: the study of chromosomes. The clas- sic work of Theodor Boveri in the 1880s provided the The science of human cytogenetics (see review by foundation for understanding chromosomes as the units of Smeets255) is attributed to the Austrian cytologist Walther inheritance, their involvement in embryonic development, Flemming, who published the first illustration of the and later, their role in disease. He postulated that chromo- human chromosome in 1882. Six years later, in 1888, somal changes could lead to the development of cancer. In Waldeyer introduced the term “chromosome.” Sutton later 1959, the first human karyotypes prepared from peripheral lymphocytes were visualized by Hungerford and col- 109 Abbreviations used in this paper: ACTH = adrenocorticotropic leagues. The ability to visualize numerical and structural hormone; BAC = bacterial artificial chromosome; CGAP = Cancer chromosomal abnormalities helped reveal the genetics of Genome Anatomy Project; CGH = comparative genomic hybridiza- Down syndrome (trisomy 21), Turner syndrome (45,X), tion; CI = confidence interval; CNS = central nervous system; and Klinefelter syndrome (47,XXY).255 DAPI = 4,6Ј-diamino-2-phenylindole-dihydrochloride; DNET = Cancer cytogenetics took a major leap in the late 1960s dysembryoplastic neuroepithelial tumor; EGFR = epidermal with studies of hematological malignancies, which finally growth factor receptor; FISH = fluorescence in situ hybridization; led to the discovery of the Philadelphia chromosome G-banding = Giemsa banding; GBM = glioblastoma multiforme; (Ph),180 which was later found to be a consistent chromoso- GH = growth hormone; LOH = loss of heterozygosity; NF1, NF2 = mal change among chronic myelogenous leukemias.230 neurofibromatosis Types 1 and 2; PCR = polymerase chain reac- tion; PNET = primitive neuroectodermal tumor; PNST = peripher- These findings provided the impetus to identify consistent/ al nerve sheath tumor; PRL = prolactin; SKY = spectral karyotyp- recurrent/nonrandom chromosomal changes in various dis- ing; TMA = tissue microarray; TSH = thyroid-stimulating ease conditions, yielding a plethora of simple and complex hormone; WHO = World Health Organization. structural and numerical cytogenetic aberrations. Neurosurg. Focus / Volume 19 / November, 2005 1 Unauthenticated | Downloaded 09/30/21 07:01 AM UTC J. Bayani, A. Pandita, and J. A. Squire The development of reliable cloning strategies in the We also refer to the NCI and NCBI’s SKY/M-FISH and 1980s facilitated the genomic analysis and sequencing of CGH Database (2001) (http://www.ncbi.nlm.nih.gov/sky/ specific DNA fragments. In addition, improvements in flu- skyweb.cgi); the Progenetix CGH online database (http:// orescence microscopy permitted the visualization of these www.progenetix.net/); and PubMed/Medline (http://www. cloned DNA fragments to the chromosomal target. The ncbi.nlm.nih.gov/entrez/query.fcgi). Readers are encouraged emergence of FISH in the late 1980s and early 1990s paved to visit these websites regularly for updates. the way for an effective and direct means of mapping spe- cific DNA fragments to their chromosomal locations.275 Be- sides being used as an important tool for gene mapping, CYTOGENETIC FINDINGS IN BRAIN FISH was also applied to ascertain the presence, absence, NEOPLASMS copy number, or location(s) of a particular chromosomal lo- cus/gene in cancer cells. The FISH analysis could be Neuroepithelial Tumors of the CNS: Glial Tumors applied not only to chromosomes (metaphase-based FISH), Astrocytic Tumors. Astrocytic tumors comprise the but to the interphase nuclei (interphase-based FISH) of cul- largest and most common group of brain tumors. The sub- tured specimens, as well as to cells from tissues embedded categories of astrocytic tumors included in this review are in paraffin, touch preparations, or smears. as follows: astrocytomas, anaplastic astrocytomas, GBM, The complexities and heterogeneity of karyotypes in pilocytic astrocytomas, subependymal giant cell astrocy- some cancers forced investigators to find means of deter- tomas, and pleomorphic xanthoastrocytomas. mining the overall genomic changes in a given tissue. The difficulty in obtaining good cytogenetic preparations from Astrocytomas, Anaplastic Astrocytomas, and GBMs. the majority of solid tumors led to the development of the This group of glial tumors illustrates the potential for low- two types of CGH assays: metaphase- and (micro)array- grade astrocytomas to progress to a more malignant pheno- based CGH. Comparative genomic hybridization is a two- type, and corresponds to the WHO grading of CNS tumors color FISH-based125 or array-based3 method used to identi- based on their histological features. Astrocytomas (WHO fy the net gains and losses of genomic material in a given Grade II) are also known as low-grade diffuse astrocytomas DNA sample. Equal amounts of tumor and normal DNA and are characterized by slow growth and infiltration of are differentially labeled, denatured, and hybridized to a neighboring brain structures. Anaplastic astrocytomas normal metaphase spread or cloned DNA arrayed on glass (WHO Grade III), also known as malignant and high-grade slides. Any deviation in the ratio from 1 denotes gains or astrocytomas, may arise from a diffuse astrocytoma or de losses of those regions in the tumor DNA. This technique, novo with no indication of a less malignant precursor. Glio- which has enabled researchers to identify common regions blastomas or GBM (WHO Grade IV) may develop from a of gain, loss, or high-level amplification without the need diffuse or an anaplastic astrocytoma (termed secondary for actively dividing cells to provide metaphase spreads, is GBM), but more commonly present de novo with no evi- usefully applied to DNAs retrieved from archived material. dence of a less malignant precursor (termed primary GBM). Although these methods proved to be useful in revealing The major genetic determinants that distinguish these two patterns of genomic alterations among different tumors, the types of GBMs are EGFR amplification and TP53 muta- information regarding the way in which these genomic tion,110 with the first being predominantly associated with changes were exhibited (that is, simple deletions/balanced the spontaneous variant, and the latter being primarily asso- translocations compared with complex rearrangements/un- ciated with GBMs arising from malignant progression. balanced translocations) in the karyotype was lost. The Because progression toward malignancy typically arises structural configurations in which amplifications, gains, from a precursor lesion, low- and high-grade astrocytomas and deletions were occurring could provide clues to the share similar changes. Classic cytogenetic analyses have mechanisms influencing or causing these chromosomal al- revealed that karyotypes range from being karyotypically terations. In the past, the numerical and structural com- normal to grossly abnormal in structure and chromosome plexities of certain cancers made G-banding descriptions number. A general observation has been that the progres- often incomplete and prone to errors. In the late 1990s sion in malignancy is concomitant with an increase in com- SKY, a multicolor FISH assay, was developed;247 this tech- plexity, both in structure and ploidy.25 nique permitted the visualization of the entire genome in A survey of the CGAP site (http://cgap.nci.nih.gov/ one experiment (for review see Bayani
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