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Analysis of the Functional Role of Chromosome 10 Loss in Human Glioblastomas1

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Analysis of the Functional Role of Chromosome 10 Loss in Human Glioblastomas1 (CANCER RESEARCH 53. 5043-5050. October 15. 1993] Analysis of the Functional Role of Chromosome 10 Loss in Human Glioblastomas1 Mark A. Pershouse, Elton Stubblefield, Azra Hadi, Ann M. Killary, W. K. Alfred Yung, and Peter A. Steck2 Departments of Neuro-Oncohfy /M. A. P., A. H., W. K. A. Y., P. A. S.], Genetics ¡E.S.¡,and Laboratory Medicine ¡A.M. K.¡,and The Brain Tumor Center ¡M.A. P., A. H.. W. K. A. Y., P. A. S./, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 ABSTRACT tumor suppressor gene in neoplasia. However, the frequent loss of an entire copy of chromosome 10 or large segments of the chromosome Molecular and cytogenetic analyses of primary brain tumors have has made localization of regions harboring a suspected tumor sup shown that losses on chromosome 10 occur very frequently in human glioblastoma multiforme suggesting the presence of a glioma-associated pressor gene difficult to identify. Various studies have identified sev eral potential regions of consistent loss: lOp (14), l()p to 10q23 (12) tumor suppressor gene on this chromosome. To examine this hypothesis, a copy of chromosome 10 derived from a human fibroblast cell line was and 10q22 to qter (13, 14). However, these suspected regions are introduced into the human glioma cell line I 251 by microcell-mediated based on relatively few informative cases. The lack of common re chromosomal transfer. A human chromosome 2 was also independently gions of structural chromosomal abnormalities or chromosomal alter introduced into I 251 cells. The presence of novel chromosomes or chro ations has slowed progress in the search for the tumor suppressor mosomal fragments was confirmed by molecular and karyotypic analyses. gene(s) on chromosome 10 in GBMs. The hybrid clones containing a transferred chromosome 10 exhibited a One approach to demonstrating the existence and possible chromo suppression of their transformed and tumorigenic phenotype in vivo and somal localization of tumor suppressor genes involves introduction of in vitro, whereas cells containing a transferred chromosome 2 failed to a specific chromosome or chromosomal fragment into the appropriate alter their phenotype. The hybrid cells containing a transferred chromo tumor cells by microcell-mediated chromosomal transfer (15-24). The some 10 displayed a significant decrease in their saturation density and an altered cellular morphology at high cell density but only a slight decrease resulting hybrid cells are then examined for the expression of an in their exponential growth rate. A dramatic decrease was observed in the altered tumorigenic phenotype compared with the parental tumor ability of cells with an introduced chromosome 10 to grow in soft agarose. cells. This approach has been used to functionally demonstrate that the The introduction of chromosome 10 completely suppressed tumor forma majority of chromosomes previously implicated through molecular tion when the hybrid cells were injected into nude mice. These findings and cytogenetic studies do contain genes that suppress the tumorige- indicate that chromosome 10 harbors a tumor suppressor gene that is nicity of various types of human tumor cells (15-19). Fragmentation directly involved in glioma oncogenesis. of the chromosome, followed by insertion of the fragments individu ally, has then served to localize the suspected tumor-suppressive re INTRODUCTION gion (16). However, not all candidate chromosomes or chromosomal GBM1 is the most frequent and malignant primary brain tumor with regions suppress growth when introduced into tumor cells (22). This a median posttreatment survival of less than 1 year. Evidence for the observation suggests the need to investigate other possible roles for activation of oncogenes and loss of function of tumor suppressor deleted or mutated genes, such as promoting differentiation or medi genes in this disease has been suggested from various studies. Fre ating the invasive properties of various cancers. quent nonrandom cytogenetic alterations observed in GBMs include In the current study, we examined the possible biological signifi an increased copy number of chromosome 7, alterations in chromo cance of the observed deletions on chromosome 10 by introducing chromosome 10 into a glioma cell line, U251, by microcell-mediated somes 9 and 22, and partial deletions in or loss of an entire copy of chromosome 10 (1, 2). Molecular analyses of GBMs have revealed the chromosomal transfer. The presence of novel chromosome 10 material amplification and rearrangement of the epidermal growth factor re was demonstrated by cytogenetic and molecular methods. Further ceptor gene, which maps to chromosome 7, as well as alterations to its more, the hybrid cells containing chromosome 10 suppressed their protein product (3, 4). Additionally, RFLP analyses have identified ability to grow in soft agar and in nude mice compared with U251 loss of heterozygosity for specific alíeleson chromosome 9 near the cells and hybrids containing a transferred chromosome 2. The results interferon a and ßgene locus (5-7), deletions and mutations in 17p suggest that chromosome 10 contains a tumor suppressor gene that inhibits both the in vitro and in vivo tumorigenic phenotype of GBM- near or at the p53 gene locus (8, 9), and extensive losses involving chromosome 10 (10-14). derived cells. The deletions on chromosome 10 appear to be the most frequent chromosomal alteration observed in GBMs with 60 to 95% of infor MATERIALS AND METHODS mative cases exhibiting loss of heterozygosity ( 1, 10, 13,14). In recent studies, approximately two-thirds of the GBMs examined had lost an Cells and Cell Culture. The U251-MG cells (referred to as U251) were entire copy of chromosome 10 and another 25% had lost large regions obtained from American Type Culture Collection (Rockvillc. MD) and were of the chromosome (13, 14). Consistent cytogenetic abnormalities and originally derived from a male patient with a GBM (25). Two different mouse allelic losses implicate the possible localization and involvement of a A9 somatic cell hybrids containing individual human chromosome 2 [HA(2)A cells] or chromosome IO (HA-38 cells) were obtained from Dr. Killary lo be used as the microcell donors. Both human chromosomes were from a diploid Received 5/27/93; accepted 8/11/93. human fibroblast cell line and had been tagged with the neomycin resistance The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with gene by a process similar to those described previously (26, 27). About one- 18 U.S.C. Section 1734 solely to indicate this fact. fifth of the HA-38 cells were also observed to contain a copy of human 1Supported in part by National Cancer Institute Grants ROI CA56041, R55 CA5604I, chromosome 22. HA(1())A cells were subsequently derived from HA-38 cells and ROI CA51I48; a grant from The Gilland Foundation: and Cancer Center Core Grant NCI CA-16672. by microcell mediated chromosomal transfer into A9 cells and were shown to 2 To whom requests for reprints should he addressed, at Department of Neuro-Oncol- contain only a single copy of human chromosome 10. All cell lines were routinely grown in Dulhecco's modified minimal essen ogy. The University of Texas M. D. Anderson Cancer Center. Box 316. 1515 Holcomhe BlOd., Houston, TX 77030. tial medium:Ham's F-12 medium (1:1) and supplemented with 5% fetal bovine ' The abbreviations used are: GBM, glioblastoma multiforme: RFLP. restriction frag ment length polymorphism; DME. Dulbecco's modified minimal essential medium; SSC, serum (Hyclone Laboratories, Logan. UT) with no antibiotics. The HA(2)A, standard saline citrate; SDS, sodium dodccyl sulfate; PCR. polymcrasc chain reaction; HA(10)A, and HA-38 cells were maintained in the presence of 400 /J.g/ml of FISH, fluorescent in .v/'/whybridization. G418 (GIBCO, Grand Island, NY). Cells were harvested with 0.25% trypsin 5043 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1993 American Association for Cancer Research. CHROMOSOME 10 LOSS IN OLIOMAS and 2 min EDTA in Ca2+- and Mg2+-free phosphate-buffered saline and cell Tumorigenicity Assays. To determine tumorigenic potential, cells at pas numbers were determined using a hemacytometer. The hybrid clones contain sages 8-12 were trypsinized and assayed for viability by trypan blue exclusion, ing chromosome 10 were subcultured at a ratio of approximately 1:4. while the and 2 X IO6or 10 X IO6cells in 0.1 ml of serum-free DME:F-12 medium were parental U251 and hybrid cells with chromosome 2 were subcultured at 1:10. inoculated s.c. into 5-6-week old athymic BALB/c-;iw//iM (nude) mice. Ani Anchorage-independent colony forming assays in semisolid medium were mals were examined for tumor formation weekly for over 1 year. Tumors and performed as described previously (28). The cells were routinely monitored for injection sites, in the case of no macroscopically observable tumor, were the absence of Mycoplasma contamination. examined and sterilely dissected from euthanized animals. Portions of tumor Microcell-mediated Chromosomal Transfer. Microcells bearing chromo were cultured in DME:F-12 medium containing 5% fetal bovine serum. Tu somes from the donor cell lines HA-38 and HA(2)A were generated by minor mors formed from hybrid cells containing an introduced chromosome 2 tagged modifications of the procedure described previously (29, 30). Briefly, mitotic with the neomycin resistance gene were cultured in the presence of G418 (200 cells were obtained from log-phase donor cells exposed to Colcemid (0.1 /¿g/ml),and cellular viability was determined. fig/ml) for 24 h and then the mitotic cells were physically dislodged and collected by centrifugation at 200 x g for 4 min. The cell pellet was resus- RESULTS pended in Percolliculture medium (1:1) containing cytochalasin B to a final concentration of 20 (xg/ml.
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