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High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray

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High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray Published OnlineFirst May 12, 2009; DOI: 10.1158/1541-7786.MCR-08-0270 Published Online First on May 12, 2009 High-Resolution Genomic Copy Number Profiling of Glioblastoma Multiforme by Single Nucleotide Polymorphism DNA Microarray Dong Yin,1 Seishi Ogawa,3 Norihiko Kawamata,1 Patrizia Tunici,2 Gaetano Finocchiaro,4 Marica Eoli,4 Christian Ruckert,6 Thien Huynh,1 Gentao Liu,2 Motohiro Kato,3 Masashi Sanada,3 Anna Jauch,5 Martin Dugas,6 Keith L. Black,2 and H. Phillip Koeffler1 1Division of Hematology/Oncology and 2Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California; 3Regeneration Medicine of Hematopoiesis, University of Tokyo, School of Medicine, Tokyo, Japan; 4National Neurological Institute “C Besta,” Milan, Italy; 5Institute of Human Genetics, University Hospital Heidelberg, Germany; and 6Department of Medical Informatics and Biomathematics, University of Munster, Munster, Germany Abstract growth factor receptor/platelet-derived growth factor receptor Glioblastoma multiforme (GBM) is an extremely malignant α. Deletion of chromosome 6q26-27 often occurred (16 of 55 brain tumor. To identify new genomic alterations in GBM, samples). The minimum common deleted region included genomic DNA of tumor tissue/explants from 55 individuals PARK2, PACRG, QKI,and PDE10A genes. Further reverse and 6 GBM cell lines were examined using single nucleotide transcription Q-PCR studies showed that PARK2 expression polymorphism DNA microarray (SNP-Chip). Further gene was decreased in another collection of GBMs at a expression analysis relied on an additional 56 GBM samples. frequency of 61% (34 of 56) of samples. The 1p36.23 region SNP-Chip results were validated using several techniques, was deleted in 35% (19 of 55) of samples. Notably,three including quantitative PCR (Q-PCR),nucleotide sequencing, samples had homozygous deletion encompassing this site. and a combination of Q-PCR and detection of microsatellite Also,a novel internal deletion of a putative tumor suppressor markers for loss of heterozygosity with normal copy number gene, LRP1B,was discovered causing an aberrant protein. [acquired uniparental disomy (AUPD)]. Whole genomic AUPDs occurred in 58% (32 of 55) of the GBM samples and DNA copy number in each GBM sample was profiled by five of six GBM cell lines. A common AUPD was found at SNP-Chip. Several signaling pathways were frequently chromosome 17p13.3-12 (included p53 gene) in 13 of 61 abnormal. Either the p16(INK4A)/p15(INK4B)-CDK4/6-pRb or samples and cell lines. Single-strand conformational p14(ARF)-MDM2/4-p53 pathways were abnormal in 89% polymorphism and nucleotide sequencing showed that 9 of (49 of 55) of cases. Simultaneous abnormalities of both 13 of these samples had homozygous p53 mutations, pathways occurred in 84% (46 of 55) samples. The suggesting that mitotic recombination duplicated the phosphoinositide 3-kinase pathway was altered in 71% (39 of abnormal p53 gene,probably providing a growth advantage 55) GBMs either by deletion of PTEN or amplification of to these cells. A significantly shortened survival time was epidermal growth factor receptor and/or vascular endothelial found in patients with 13q14 (RB) deletion or 17p13.1 (p53) deletion/AUPD. Taken together,these results suggest that this technique is a rapid,robust,and inexpensive method to profile genome-wide abnormalities in GBM. (Mol Cancer Res Received 6/11/08; revised 1/13/09; accepted 1/30/09; published OnlineFirst 5/12/09. 2009;7(5):665–77) Grant support: NIH, Tom Collier Foundation, Parker Hughes Trust, the Inger Fund, and the Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center. Introduction The costs of publication of this article were defrayed in part by the payment of Glioblastoma multiforme (GBM) is an extremely malignant page charges.This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. subtype of astrocytoma, with survival times being <12 to 15 Note: K.L. Black and H.P. Koeffler contributed equally to this work and should months.These tumors typically have a very high proliferative be considered co–last authors.H.P.Koeffler is a member of the Molecular rate with widespread microvascular proliferation and areas of Biology Institute and Jonsson Comprehensive Cancer Center at the University of California at Los Angeles and holds the endowed Mark Goodson Chair of focal necrosis.Genetic abnormalities have been identified in Oncology Research at Cedars-Sinai Medical Center/University of California at GBM using cytogenetics, fluorescence in situ hybridization, Los Angeles School of Medicine.This work is in loving memory of Matt and comparative genomic hybridization.These studies have Schreck. Requests for reprints: Dong Yin, Division of Hematology and Oncology, shown several notable abnormalities.The p16(INK4A)/p15 Cedars-Sinai Medical Center, University of California at Los Angeles School (INK4B)-CDK4/6-pRb pathway was found to be aberrant in of Medicine, Davis Building 5022 Room, 8700 Beverly Boulevard, Los Angeles, CA 90048.Phone: 310-423-7740; Fax: 310-423-0225.E-mail: Dong. the vast majority of GBMs either as a result of inactivation [email protected] and Seishi Ogawa, Regeneration Medicine of Hematopoiesis, of either p16(INK4A) or Rb or overexpression of either School of Medicine, University of Tokyo, Tokyo, Japan.E-mail: sogawa-tky@ CDK4 or CDK6 (1, 2).Homozygous deletion of p16(INK4A) umin.ac.jp Copyright © 2009 American Association for Cancer Research. occurs in approximately 31% to 50% of GBMs (3, 4).The doi:10.1158/1541-7786.MCR-08-0270 CDK4 gene is amplified on chromosome 12q13-14 in ∼15% Mol Cancer Res 2009;7(5). May 2009 665 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst May 12, 2009; DOI: 10.1158/1541-7786.MCR-08-0270 666 Yin et al. of GBM (1).The long arm of chromosome 13 is lost in nearly Table 1. Common Minimal Region of Deletion,Amplification, 33% to 50% of these tumors; the Rb gene is at least one of the and Acquired Uniparental Disomy targets in this deletion, being inactivated in ∼35% of samples Minimal Region No. Selected Genes Within the Region (5-8).Loss of chromosomal material on chromosome 10 occurs Affected in 60% to 95% of GBMs (9).One common minimum deleted Samples (%) region (CMDR) at 10q23.3 includes the PTEN gene, which oc- curs in approximately 20% to 30% of samples (10-12).Epider- CMDR 1p36.23 (1,720 kb) 19/55 (35%), CAMTA1, PER3, UTS2, TNFSF9, mal growth factor receptor (EGFR)isamplifiedin∼40% of 16 D and 3 DD VAMP3, PARK7, MIG6, RERE, GBMs (9).Of interest, 33% of these tumors with EGFR ampli- GPR157, H6PD EGFR 2q22.1 (479 kb) 4/55 (7%), 4D LRP1B fication have a specific rearrangement, producing a 6q 26-27 (3,133 kb) 16/55 (29%), PARK2, PACRG, QKI, PDE10A smaller protein, making it similar to the v-erbB oncogene 14 D and 2 DD (13).Amplification of EGFR is associated with overexpression 9p21.3 36/55 (66%), p14(ARF), p15(INK4B), (981 kb) 16 D and 20 DD p16(INK4A) of the EGFR protein and it is often associated with deletion of 10q23.31 33/55 (60%), PTEN PTEN and p16(INK4A) (14).Alterations of chromosome 17p (693 kb) 31 D and 2 DD are associated with a mutation of the p53 gene in ∼30% of 13q14.2-14.3 22/55 (40%), Rb, KCNRG (1,987 kb) 21 D and 1 DD GBMs.The prominent vascularity that occurs in GBM is prob- 17p 13.1 10/55 (18%), 10 D p53 ably the result of excess expression of growth factors and their (636 kb) CMAR receptors [e.g., vascular growth factor receptor (VEGFR) and 1q32.1 7/55 (13%), MDM4, NFASC, LRRN5 platelet-derived growth factor receptor (PDGFR)] that are asso- (758 kb) 4A and 3 AA ciated with angiogenesis. 4q11-12 5/55 (9%), PDGFRA, KIT, VEGFR, CLOCK (3,157 kb) 2Aand3AA We used high-density (50K/250K) arrayed oligonucleotide 7p11.2 36/55 (66%). EGFR probes that contain single nucleotide polymorphisms (SNP), (660 kb) 19 A and 17 AA the so-called SNP-Chip, to identify genetic abnormalities, in- 12q14.1 6/55 (11%), 6 AA CDK4 (390 kb) cluding amplicons, duplications, deletions, and acquired uni- 12q15 6/55 (11%), 6 AA MDM2 parental disomy [AUPD; loss of heterozygosity (LOH) with (795 kb) AUPD normal copy number].Our SNP-Chip results were validated 17p 13.3-12 8/55 (15%) p53 using several other techniques, including quantitative PCR (10,700 kb) (Q-PCR), nucleotide sequencing, and detection of LOH by microsatellite markers.Using SNP-Chips, we identified aber- NOTE: D, heterozygous deletion; DD, homozygous deletion; A, trisomy; AA, high-level copy number amplifications. rant genes as well as aberrant genetic pathways in GBM. This robust technology should set the stage to formulate new diagnostic subcategorizations of GBM and to provide GBM patients, survival data were available.Median survival prognostic indicators for physicians to set up personalized time was 60 weeks.Overall, 39 events were reported.Signif- therapy according to the aberrant genetic pattern of the icant short survival time (P values were not corrected for GBM of the individual. multiple testing) was found in the patients with 13q14 (RB) deletion (Fig.1E) or 17p13.1( p53) deletion/AUPD (Fig.1F).In these CMDR and CMAR, the genes involve in Results the p16(INK4A)/p15(INK4B)-CDK4/6-pRb (pathway 1) and Signaling Pathway Abnormalities Present in GBM the p14(ARF)-MDM2/4-p53 (pathway 2) were frequently DNA from 55 GBMs (22 with matched normal peripheral aberrant: pathway 1 had deletion of p16(INK4A) and p15 blood neutrophils) and 6 GBM cell lines were examined by (INK4B) in 66% of cases; deletion of Rb in 40% of cases; SNP-Chip assay for genomic abnormalities (Tables 1 and 2).
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